linoleic-acid and Disease-Models--Animal

Atopic dermatitis (AD) is a common pruritic chronic skin disease. AD pathogenesis remains elusive, but may involve complex interplays among skin barrier dysfunction, Th2 inflammation, and pruritus. Current treatments for AD are still limited to symptomatic therapies. We previously showed that HR-1 hairless mice fed a special diet (HR-AD) develop AD-like symptoms; however, the ingredient(s) causing dermatitis remain unclear. In this study, we examined whether the deficiency of certain polyunsaturated fatty acids (PUFAs) was involved in the diet-induced AD pathogenesis. In the serum of HR-AD-fed mice, levels of linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), as well as their metabolites, were markedly decreased. HR-AD-induced AD symptoms were significantly ameliorated by LA supplementation, and to a lesser extent by ALA supplementation. In addition, LA metabolites, such as γ-linolenic acid and arachidonic acid, had effects similar to those of LA. Further, using semi-purified custom diets, we attempted to reproduce HR-AD-induced AD symptoms. Unexpectedly, a deficiency in unsaturated fatty acids (UFAs) alone caused mild symptoms. However, several modifications of fat and carbohydrate components in the diet revealed that dietary deficiencies of UFA and cornstarch were required to fully induce severe AD symptoms. Furthermore, we examined the influence of genetic background on the development of diet-induced AD and found that a hypomorphic mutation in the hairless gene Hr, encoding a nuclear receptor (NR) corepressor, was essential for the complete development of diet-induced pruritic atopic skin. Thus, our findings suggest that certain PUFAs and NRs are new, potential therapeutic targets for treating AD.

Topics: Animals; Co-Repressor Proteins; Dermatitis, Atopic; Diet; Disease Models, Animal; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Mice, Hairless; Molecular Targeted Therapy; Mutation; Starch; Transcription Factors

The "modern western" diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

Topics: Animals; Black or African American; Cardiovascular Diseases; Diet; Disease Models, Animal; Fatty Acids, Omega-6; Gene-Environment Interaction; Health Status Disparities; Humans; Linoleic Acid; Risk Factors

Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. Evidence indicates that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. A new mechanism by which physiological and pharmacological blood levels of melatonin inhibit cancer growth in vivois via a melatonin-induced suppression of tumor linoleic acid (LA) uptake and its metabolism to the important mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin suppresses cAMP formation and inhibits tumor uptake of LA and its metabolism to 13-HODE via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. It has been postulated that in industrialized societies, light at night, by suppressing melatonin production, poses a new risk for the development of breast cancer and, perhaps, other cancers as well. In support of this hypothesis, light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of rat hepatoma and human breast cancer xenografts. Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth via the mechanisms described above. The nocturnal melatonin signal organizes tumor metabolism and growth within circadian time structure that can be further reinforced by appropriately timed melatonin supplementation. Dietary melatonin supplementation working in concert with the endogenous melatonin signal has the potential to be a new preventive/therapeutic strategy to optimize the host/cancer balance in favor of host survival and quality of life.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Circadian Rhythm; Dietary Supplements; Disease Models, Animal; Humans; Light; Linoleic Acid; Melatonin; Neoplasms; Sleep

Conjugated Linoleic Acids (CLA) are of great interest for analysts since techniques have been developed to determine the dietary occurrence of CLA with a good accuracy. CLA is found in animal products from ruminant sources as the result of biohydrogenation of polyunsaturated fatty acids in the rumen and as the consequence of the delta-9 desaturation of vaccenic acid in animal tissues. CLA can also be obtained in the laboratory by isomerisation of linoleic acid or by total chemical synthesis. While the "natural" isomer is rumenic acid (9c,11t-18:2), synthetic mixtures contain mainly two isomers: the 9c,11t- and the 10t,12c-18:2. Although CLA have been shown to be metabolized into desaturated and chain elongated products, it remains unclear whether these so-formed conjugated metabolites may be involved in the effects of CLA on fatty acid metabolism. Experiments carried out on animal models with CLA have shown different health benefits: anticarcinogenic, antiatherosclerotic effects, modulation of body composition , the "natural" CLA (9c,11t-18:2) being closely related to the protection against cancer and the 10t,12c-18:2 to the reduction of the fat mass. Nevertheless, recent findings have suggested adverse effects in mice. Most of the studies carried out on humans concern the influence of CLA on body composition and its possible inverse association with cancer. Since the results are still controversial and since very few data dealing with the safety of using CLA in long term feeding studies have so far been published, further works are warranted to consider the benefits of CLA for humans.

Topics: Animals; Arteriosclerosis; Body Composition; Disease Models, Animal; Humans; Linoleic Acid; Linoleic Acids, Conjugated; Neoplasms; Oleic Acids; Trans Fatty Acids

Conjugated linoleic acid (CLA) is composed of positional and stereoisomers of octadecadienoate (18:2); it is found in foods derived from ruminants (beef and lamb as well as dairy products from these sources). When a mixture of isomers is fed to experimental animals, chemically induced tumorigenesis of mammary, skin and colon is reduced. Importantly, many isomers of CLA are readily metabolized to desaturated/elongated products as well as beta-oxidized products, suggesting that these metabolites may be important anticancer compounds. Mechanisms of inhibition of carcinogenesis may include reduction of cell proliferation, alterations in the components of the cell cycle and induction of apoptosis. In addition, CLA modulates markers of immunity and eicosanoid formation in numerous species as well as lipid metabolism and gene expression. It is likely that CLA exerts inhibitory properties in carcinogenesis via one or more of these pathways with some tissue specificity. This review will explore recent advances in putative mechanisms of reduction of carcinogenesis by CLA.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Division; Dairy Products; Disease Models, Animal; Eicosanoids; Fatty Acids, Unsaturated; Gene Expression Regulation, Neoplastic; Humans; Isomerism; Linoleic Acid; Lipid Metabolism; Meat; Neoplasms, Experimental; Ruminants

Conjugated linoleic acid (CLA) is a mixture of positional (e.g. 7,9; 9,11; 10,12; 11,13) and geometric (cis or trans) isomers of octadecadienoic acid. This compound was first shown to prevent mammary carcinogenesis in murine models. Later investigations uncovered a number of additional health benefits, including decreasing atherosclerosis and inflammation while enhancing immune function. The mechanisms of action underlying these biological properties are not clearly understood. The aim of this review is to highlight recent advances in CLA research related to experimental inflammatory bowel disease. In addition, two possible mechanisms of action (i.e. endoplasmic and nuclear) were discussed in detail in the context of enteric inflammatory disorders. Conjugated linoleic acid was first implicated in down-regulating the generation of inducible eicosanoids (i.e. PGE(2) and LTB(4)) involved in early micro-inflammatory events (endoplasmic). More recently, CLA has been shown to modulate the expression of genes regulated by peroxisome proliferator-activated receptors (PPARs; nuclear). In pigs, prolonged dietary CLA treatment stimulated the expression of PPAR-gamma in the muscle. Thus, evidence supporting both mechanistic theories of CLA acting through eicosanoid synthesis and PPAR activity is available. The further understanding of the anti-inflammatory mechanisms of action of CLA may yield novel nutritional therapies for enteric inflammation.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Disease Models, Animal; Eicosanoids; Gene Expression Regulation; Humans; Inflammatory Bowel Diseases; Isomerism; Linoleic Acid; Mice; Receptors, Cytoplasmic and Nuclear; Swine; Transcription Factors

Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids found in beef, lamb, and dairy products that exist as positional and stereo-isomers of octadecadienoate (18:2). Over the past two decades numerous health benefits have been attributed to CLA in experimental animal models including actions to reduce carcinogenesis, atherosclerosis, onset of diabetes, and body fat mass. The accumulation of CLA isomers and several elongated/desaturated and beta-oxidation metabolites have been found in tissues of animals fed diets with CLA. Molecular mechanisms of action appear to include modulation of eicosanoid formation as well as regulation of the expression of genes coding for enzymes known to modulate macronutrient metabolism. This review focuses on health benefits, metabolism, and potential mechanisms of action of CLA and postulates the implications regarding dietary CLA for human health.

Topics: Adipose Tissue; Animals; Arteriosclerosis; Dairy Products; Diabetes Mellitus; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Humans; Linoleic Acid; Meat; Mice; Neoplasms; Rats; Stereoisomerism

The underlying etiology of the toxic oil syndrome may be related to any of several toxic contaminants. The hypothesis is made that two or more toxic compounds may act synergistically to cause vascular damage in the toxic oil syndrome. To support this hypothesis, previous studies are reviewed concerning the remarkable synergistic toxic action of allylamine and beta-aminopropionitrile on the media of blood vessels. Although these toxins are not directly related to the toxic oil syndrome, this previous experimental work emphasizes the possibility that unexplored synergistic actions may be important. Furthermore, the hypothesis that contaminating fatty acid anilides in toxic oil undergo alterations during cooking is supported by high pressure liquid chromatographic analysis. The theoretic metabolism of fatty acid anilides is discussed. Recent data concerning the toxic actions of the anilides of oleic and linoleic acid are given. These data suggest that these anilides induce immunologic alterations that may be similar to those seen in the toxic oil syndrome. In addition, the heated anilides appear to have increased toxicity, supporting the concept that the use of toxic oil in cooking may increase its toxicity.

Topics: Allylamine; Aminopropionitrile; Anilides; Animals; Brassica; Cooking; Disease Models, Animal; Drug Synergism; Fatty Acids; Linoleic Acid; Linoleic Acids; Oleic Acid; Oleic Acids; Oxidation-Reduction; Plant Oils; Rats; Rats, Inbred Strains; Vascular Diseases

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.

Topics: Alleles; Angelman Syndrome; Animals; Disease Models, Animal; Female; Humans; Intellectual Disability; Ion Channels; Linoleic Acid; Male; Mice

Gastric ulcer has been a major cause of morbidity and mortality worldwide, and it has been linked to factors such as nutritional deficiency, smoking, stress, and continuous intake of non-steroidal antiinflammatory drugs (NSAIDs). The search for new anti-ulcer therapeutic agents has been the subject of several studies. Recently, the gastroprotective effect of Celtis iguanaea has been reported, with linoleic acid (LA) responsible for many of the therapeutic effects of this medicinal plant.. This study aims to investigate the gastroprotective activity and the possible mechanisms in which LA may be involved through different experimental assays in mice.. The gastroprotective activity of LA was evaluated in the ulcer induced by indomethacin, HCl/EtOH, hypothermic-restraint stress and pyloric ligation. For the investigation of gastroprotective mechanisms, the quantification of the volume (mL), pH and total acidity of gastric secretion were considered.. The oral administrations of 25 mg/kg, 50 mg/kg or 100 mg/kg of body weight of LA were capable of protecting the gastric mucosa against HCl/ethanol (10 mL/kg p.o.), and oral/intraduodenal treatment administrations of 50 mg/kg LA showed protection from ulcers induced by indomethacin, hypothermic-restraint stress and pyloric ligation.. The results of this study show the gastroprotective role of LA in gastric mucosal damage induced by all assayed distresses. The observed gastroprotection possibly occurs due to the mediated increase of mucosal defensive factors.

Topics: Animals; Anti-Ulcer Agents; Disease Models, Animal; Ethanol; Gastric Mucosa; Humans; Indomethacin; Linoleic Acid; Mice; Plant Extracts; Stomach Ulcer

Obesity is a major cause of non-alcoholic fatty liver disease (NAFLD). NAFLD is an epidemic affecting nearly 34% of the adult population in the US. As a chronic inflammatory disease, NAFLD influences the immune system by dysregulating T-cell activity. Remedies for the adverse effects on the immune system are urgently needed. We studied Theaphenon E (TE), a standardized formulation of green tea extract, on the adverse effects of NAFLD in C57BL/6J mice fed a high fat diet (HFD).. Mice received HFD, low fat diet (LFD) or HFD+2% TE for 35 weeks. Hepatic lipid accumulation, cell proliferation, apoptosis and CD4+T lymphocytes were measured throughout the bioassay. The hepatic composition of fatty acids was determined. The effects of epigallocatechin gallate (EGCG) metabolites on lipid accumulation in mouse and primary human liver cells were studied.. Unlike mice receiving HFD, mice on HFD+2% TE maintained normal liver to body weight ratios with low levels of alanine and aspartate aminotransferase (ALT and AST). Hepatic lipid accumulation was observed in HFD mice, accompanied by increased proliferation, reduced apoptosis and loss of CD4+ T lymphocytes. TE significantly inhibited lipid accumulation, decreased proliferation, induced apoptosis and increased CD4+ T cell survival in HFD mice. It was found that the EGCG metabolite EGC-M3 reduced lipid accumulation in mouse and human hepatocytes. Linoleic acid showed the largest increase (2.5-fold) in livers of mice on a HFD and this increase was significantly suppressed by TE.. Livers of HFD-fed mice showed lipid accumulation, increased proliferation, reduced apoptosis, elevated linoleic acid and loss of CD4+ T cells. TE effectively ameliorated all of these adverse effects.

Topics: Animals; Apoptosis; Catechin; CD4-Positive T-Lymphocytes; Cell Proliferation; Diet, Fat-Restricted; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Hepatocytes; Humans; Linoleic Acid; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity

Topics: Actins; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Collagen; Disease Models, Animal; Drug Compounding; Drug Delivery Systems; Endopeptidases; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Linoleic Acid; Liver Neoplasms; Membrane Proteins; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Nanoparticles; NIH 3T3 Cells; Polymers; Xenograft Model Antitumor Assays

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Evidence suggests that sub-optimal maternal nutrition has implications for the developing offspring. We have previously shown that exposure to a low-protein diet during gestation was associated with upregulation of genes associated with cholesterol transport and packaging within the placenta. This study aimed to elucidate the effect of altering maternal dietary linoleic acid (LA; omega-6) to alpha-linolenic acid (ALA; omega-6) ratios as well as total fat content on placental expression of genes associated with cholesterol transport. The potential for maternal body mass index (BMI) to be associated with expression of these genes in human placental samples was also evaluated. Placentas were collected from 24 Wistar rats at 20-day gestation (term = 21-22-day gestation) that had been fed one of four diets containing varying fatty acid compositions during pregnancy, and from 62 women at the time of delivery. Expression of 14 placental genes associated with cholesterol packaging and transfer was assessed in rodent and human samples by quantitative real time polymerase chain reaction. In rats, placental mRNA expression of ApoA2, ApoC2, Cubn, Fgg, Mttp and Ttr was significantly elevated (3-30 fold) in animals fed a high LA (36% fat) diet, suggesting increased cholesterol transport across the placenta in this group. In women, maternal BMI was associated with fewer inconsistent alterations in gene expression. In summary, sub-optimal maternal nutrition is associated with alterations in the expression of genes associated with cholesterol transport in a rat model. This may contribute to altered fetal development and potentially programme disease risk in later life. Further investigation of human placenta in response to specific dietary interventions is required.

Topics: Adult; alpha-Linolenic Acid; Animals; Cholesterol; Diet, High-Fat; Disease Models, Animal; Female; Fetal Development; Gene Expression Profiling; Gene Expression Regulation, Developmental; Humans; Linoleic Acid; Maternal Nutritional Physiological Phenomena; Obesity; Placenta; Pregnancy; Rats; Real-Time Polymerase Chain Reaction

Obesity-induced inflammation, or meta-inflammation, plays key roles in metabolic syndrome and is a significant risk factor in diabetes and cardiovascular disease. To investigate causal links between obesity, meta-inflammation, and insulin signaling we established a

Topics: Animals; Animals, Genetically Modified; Cell Nucleus; Chromatin; Dietary Fats; Disease Models, Animal; Drosophila; Drosophila Proteins; Fatty Acids, Omega-3; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation; HeLa Cells; Humans; Inflammation; Insulin; Linoleic Acid; Linoleic Acids, Conjugated; Obesity; Protein Binding; Signal Transduction; Transcriptome; Transfection

Autofluorescence (AF) of crude serum was investigated with reference to the potential of its intrinsic AF biomarkers for the noninvasive diagnosis of liver injury. Spectral parameters of pure compounds representing retinol (vitamin A) and fluorescing free fatty acids were characterized by spectrofluorometry, to assess spectral parameters for the subsequent AF analysis of serum, collected from rats undergoing liver ischemia/reperfusion (I/R). Differences in AF spectral profiles detected between control and I/R were due to the increase in the AF components representing fatty acids in I/R serum samples. No significant changes occurred for retinol levels, consistently with the literature reporting that constant retinol levels are commonly observed in the blood, except for malnutrition or chronic severe liver disease. Conversely, fatty acids, in particular arachidonic and linoleic acid and their derivatives, act as modulating agents in inflammation, representing both a protective and damaging response to stress stimuli. The biometabolic and pathophysiological meaning of serum components and the possibility of their direct detection by AF spectrofluorometry open up interesting perspectives for the development of AF serum analysis, as a direct, cost effective, supportive tool to assess liver injury and related systemic metabolic alterations, for applications in experimental biomedicine and foreseen translation to the clinics.

Topics: Animals; Arachidonic Acid; Biomarkers; Disease Models, Animal; Energy Metabolism; Fatty Acids; Fluorescence; Inflammation; Ischemia; Linoleic Acid; Liver; Liver Diseases; Male; Rats; Rats, Wistar; Reperfusion Injury; Serum; Spectrometry, Fluorescence; Vitamin A

Food source has a significant impact on levels of fatty acids and their derivatives, fatty acid ethanolamides (FAEs), in the small intestine and brain. Among non-essential fatty acids, oleic acid and its FAE acutely reduce food intake. However, effects of the essential α-linolenic acid, linoleic acid, and their FAEs on appetite regulation remain undefined. This study tested the hypothesis that α-linolenic acid and linoleic acid mediate acute suppression of food intake through their corresponding FAEs, α-linolenoylethanolamide and linoleoylethanolamide, respectively. To allow for the differentiation of the effects of FAEs and their parent fatty acids, male Wistar rats were injected intraperitoneally with α-linolenic acid, linoleic acid, α-linolenoylethanolamide and linoleoylethanolamide after a 12-hour overnight fast. Short-term food intake, plasma and brain FAE status, and plasma concentrations of insulin and leptin were measured to determine whether these hormones mediate the anorectic effect of FAEs. Both ethanolamides, but not their parent fatty acids, acutely suppressed food intake up to one hour post-treatment and this effect was independent of insulin and leptin hormones. In conclusion, essential α-linolenic and linoleic fatty acids mediate acute suppression of food intake through their corresponding FAEs. These findings may aid in the further research of FAEs as potential therapeutic agents for the management and treatment of obesity.

Topics: alpha-Linolenic Acid; Animals; Disease Models, Animal; Eating; Functional Food; Linoleic Acid; Linoleic Acids; Male; Obesity; Polyunsaturated Alkamides; Random Allocation; Rats; Rats, Wistar

Topics: Angiotensin II; Animals; Aorta; Aortic Dissection; Disease Models, Animal; Endoplasmic Reticulum Stress; Group V Phospholipases A2; Linoleic Acid; Mice; Mice, Knockout; Oleic Acid; Phospholipids

In this study, we investigated the effects of linoleic acid (LA) treatment on Brucella abortus infection in professional phagocyte RAW264.7 cells, particularly during the pathogens invasion and intracellular growth in these cells, as well as in murine model BALB/c mice focusing on bacterial splenic proliferation and immunoregulatory activities. LA inhibited the growth of

Topics: Animals; Anti-Bacterial Agents; Brucella abortus; Brucellosis; Cytokines; Disease Models, Animal; Linoleic Acid; Mice; Mice, Inbred BALB C; RAW 264.7 Cells; Spleen

Lovastatin is an important medicine and it shows a significant effect against glucocorticoid-induced necrosis of the femoral head. This study aimed to investigate the effect of lovastatin on preventing necrosis of the femoral head of by serum metabolomics strategy.. Adult healthy adult Japanese white rabbits were divided into three groups: control group, model group, and drug group. The pathologic changes of femoral head were assessed with magnetic resonance imaging and microscope. Metabolomics based on ultra-high performance liquid chromatography tandem mass spectrometry analysis was used to analyze the collected serum sample. Data were analyzed using principal component analysis, partial least squares-discriminate analysis, and orthogonal partial least squares-discriminant analysis. All potential metabolites were identified by comparing with human metabolome database, Metlin database, lipid maps, and chemspider database.. Eleven potential biomarkers were noted and identified as potential biomarkers. The change of biomarkers suggested that lovastatin on preventing necrosis of the femoral head may affect glycerophospholipid metabolism, linoleic acid metabolism, sphingolipid metabolism, alpha-linolenic acid metabolism, pyrimidine metabolism, and arachidonic acid metabolism.. The study suggested that lovastatin could prevent the glucocorticoid-induced necrosis of the femoral head of rabbits. The possible reasons were closely associated with adjusting the lipid metabolism, inhibiting adipogenesis, and delaying the osteocyte apoptosis.

Topics: Adipogenesis; Animals; Apoptosis; Disease Models, Animal; Femur Head Necrosis; Glucocorticoids; Glycerophospholipids; Linoleic Acid; Lovastatin; Magnetic Resonance Imaging; Metabolomics; Osteocytes; Rabbits; Sphingolipids

In outbred mice, susceptibility or resistance to diet-induced obesity is associated with rapid changes in hypothalamic proopiomelanocortin (POMC) levels. Here, we evaluated 3 hypotheses that potentially explain the development of the different obesity phenotypes in outbred Swiss mice. First, rapid and differential changes in the gut microbiota in obesity-prone (OP) and obesity-resistant (OR) mice fed on a high-fat diet (HFD) might cause differential efficiencies in fatty acid harvesting leading to changes in systemic fatty acid concentrations that in turn affect POMC expression and processing. Second, independently of the gut microbiota, OP mice might have increased blood fatty acid levels after the introduction of a HFD, which could affect POMC expression and processing. Third, fatty acids might act directly in the hypothalamus to differentially regulate POMC expression and/or processing in OP and OR mice. We evaluated OP and OR male Swiss mice using 16S rRNA sequencing for the determination of gut microbiota; gas chromatography for blood lipid determination; and immunoblot and real-time polymerase chain reaction for protein and transcript determination and indirect calorimetry. Some experiments were performed with human pluripotent stem cells differentiated into hypothalamic neurons. We did not find evidence supporting the first 2 hypotheses. However, we found that in OP but not in OR mice, palmitate induces a rapid increase in hypothalamic POMC, which is followed by increased expression of proprotein convertase subtilisin/kexin type 1 PC1/3. Lentiviral inhibition of hypothalamic PC1/3 increased caloric intake and body mass in both OP and OR mice. In human stem cell-derived hypothalamic cells, we found that palmitate potently suppressed the production of POMC-derived peptides. Palmitate directly regulates PC1/3 in OP mice and likely has a functional impact on POMC processing.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Hypothalamus; Inflammation; Linoleic Acid; Male; Mice; Neurons; Obesity; Palmitates; Pluripotent Stem Cells; Pro-Opiomelanocortin; RNA, Ribosomal, 16S

Retinol-binding protein 4 (RBP4) serves as a transporter for all- trans-retinol (1) in the blood, and it has been proposed to act as an adipokine. Elevated plasma levels of the protein have been linked to diabetes, obesity, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). Recently, adipocyte-specific overexpression of RBP4 was reported to cause hepatic steatosis in mice. We previously identified an orally bioavailable RBP4 antagonist that significantly lowered RBP4 serum levels in Abca4

Topics: Animals; Chemistry Techniques, Synthetic; Disease Models, Animal; Drug Design; Fatty Liver; Male; Mice; Piperidines; Rats; Retinol-Binding Proteins, Plasma; Tissue Distribution

Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer's disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κB transcriptional activity resulting in NF-κB-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κB activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Disease Models, Animal; Food, Fortified; Hippocampus; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Palmitates; Peptide Fragments

Cardiac ischemia/reperfusion injury is associated with the formation and action of lipid mediators derived from polyunsaturated fatty acids. Among them, linoleic acid (LA) is metabolized to epoxyoctadecanoic acids (EpOMEs) by cytochrome P450 (CYP) epoxygenases and further to dihydroxyoctadecanoic acids (DiHOMEs) by soluble epoxide hydrolase (sEH). We hypothesized that EpOMEs and/or DiHOMEs may affect cardiac post-ischemic recovery and addressed this question using isolated murine hearts in a Langendorff system. Hearts from C57Bl6 mice were exposed to 12,13-EpOME, 12,13-DiHOME, or vehicle (phosphate buffered sodium; PBS). Effects on basal cardiac function and functional recovery during reperfusion following 20 min of ischemia were investigated. Electrocardiogram (ECG), left ventricular (LV) pressure and coronary flow (CF) were continuously measured. Ischemia reperfusion experiments were repeated after administration of the sEH-inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). At a concentration of 100 nM, both EpOME and DiHOME decreased post-ischemic functional recovery in murine hearts. There was no effect on basal cardiac parameters. The detrimental effects seen with EpOME, but not DiHOME, were averted by sEH inhibition (AUDA). Our results indicate that LA-derived mediators EpOME/DiHOME may play an important role in cardiac ischemic events. Inhibition of sEH could provide a novel treatment option to prevent detrimental DiHOME effects in acute cardiac ischemia.

Topics: Adamantane; Animals; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Isolated Heart Preparation; Lauric Acids; Linoleic Acid; Male; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Myocardium; Oleic Acids; Recovery of Function; Signal Transduction; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Arachidonic Acid; Cystic Fibrosis; Disease Models, Animal; Docosahexaenoic Acids; Female; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CFTR; Mice, Knockout

Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo.

Topics: Analgesics; Animals; Behavior, Animal; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Female; Freund's Adjuvant; Hot Temperature; Humans; Hyperalgesia; Inflammation; Linoleic Acid; Male; Mice; Oleic Acids; Oxidation-Reduction; Pain; Phenylurea Compounds; Piperidines; Protein Kinase C; Sensory Receptor Cells; TRPV Cation Channels; Zymosan

Studies have suggested the supplementation of Zinc and Linoleic acid in the management of neurodegenerative disorders but none has investigated the combined effects. Little is known about the neuroprotective effects of either Zinc or Linoleic acid or their combination against development of Parkinsonism. This study was designed to investigate the neuroprotective effects of Zinc and Linoleic acid in rotenone-induced Parkinsonism in rats.. Thirty-six young adult female rats weighing 100-150 g divided into six groups were used. Rats were induced with Parkinsonism by subcutaneous administration of rotenone (2.5 mg/kg) once a day for seven consecutive days. The rats received dimethyl sulfoxide (DMSO)/Olive oil or rotenone dissolved in DMSO/Olive oil. Groups III and IV received Zinc (30 mg/kg) or Linoleic acid (150 µl/kg) while group V received a combination of both, 2 weeks prior to rotenone injection. Groups II and VI served as negative (rotenone group) and positive (Levodopa groups) controls respectively. Oxidative stress levels were assessed by estimating Lipid peroxidation (MDA), total antioxidant capacity, Superoxide dismutase, reduced Glutathione (GSH), glutathione peroxidase and catalase in the midbrain. Histological examination was done to assess structural changes in the midbrain.. There was a significant prevention in lipid peroxidation and decrease in the antioxidant status in intervention-treated groups as compared to the rotenone treated group. In addition, histological examination revealed that Parkinsonian rat brains exhibited neuronal damage. Cell death and reduction in neuron size induced by rotenone was prevented by treatment with zinc, linoleic acid and their combination.. These results suggest that zinc and linoleic acid and their combination showed significant neuroprotective activity most likely due to the antioxidant effect.

Topics: Animals; Antioxidants; Disease Models, Animal; Female; Glutathione; Levodopa; Linoleic Acid; Lipid Peroxidation; Parkinsonian Disorders; Rats, Wistar; Rotenone; Zinc

The aim of this study was to determine the optimal weighting factor (WF) for precise quantification using six-point interference Dixon fat percentage imaging by analyzing changes in WFs of fatty acid metabolites (FMs) in high-fat-induced fatty liver disease rat model.. Individual FM-related WFs were calculated based on concentration ratios of integrated areas of seven peak FMs with four phantom series. Ten 8-week-old male Sprague-Dawley rats were used for baseline quantification of fat in liver magnetic resonance imaging or magnetic resonance spectroscopy data. These seven lipid metabolites were then quantitatively analyzed. Spearman test was used for correlation analysis of different lipid proton concentrations. The most accurate WF for six-point interference Dixon fat percentage imaging was then determined.. The seven lipid resonance WF values obtained from magnetic resonance spectroscopy data for three different oils (oleic, linoleic, and soybean) were different from each other. In lipid phantoms, except for the phantom containing oleic acid, changes in FP values were significantly different when WFs were changed in six-point interference Dixon fat percentage image. The seven lipid resonance WF values for the nonalcoholic fatty liver animal model were different from human subcutaneous adipose tissue lipid WF values.. WF affected the calculation of six-point interference Dixon-based fat percentage imaging value in phantom experiment. If WF of liver parenchyma FM which is specific to each liver disease is applied, the accuracy of six-point interference Dixon fat percentage imaging can be further increased.

Topics: Adipose Tissue; Animals; Disease Models, Animal; Linoleic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Non-alcoholic Fatty Liver Disease; Oleic Acid; Phantoms, Imaging; Rats; Rats, Sprague-Dawley; Soybean Oil

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast with traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases. Here, we investigated the effect of D-PUFA treatment in a knock-in mouse model of HD (Q140) which presents motor deficits and neuropathology from a few months of age, and progressive cognitive decline. Q140 knock-in mice were fed a diet containing either D- or H-PUFAs for 5 months starting at 1 month of age. D-PUFA treatment significantly decreased F

Topics: Animals; Body Weight; Cognitive Dysfunction; Deuterium; Dietary Supplements; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Huntingtin Protein; Huntington Disease; Linoleic Acid; Lipid Peroxidation; Male; Mice, Transgenic; Motor Activity

The potential effects of 2 types of fatty acids on colorectal cancer (CRC) were assessed using cancer stromal cells. Linoleic acid (LA; C-18, n-6 unsaturated fatty acid) and elaidic acid (EA; C-18, trans acid), both known to affect colon carcinogenesis and cancer progression, were administered by gavage to BALB/c mice, which were inoculated with CT26 syngeneic colon cancer cells in the back. Both EA and LA treatments enhanced tumor growth and metastasis. EA and LA also increased the number of CD133-positive stromal cells in the tumor capsule. Importantly, those cancer cells at the tumor periphery, physically attached to CD133-positive stromal cells, also expressed CD133. These findings suggest that EA and LA might induce stemness in cancer cells through physical association and promote cancer metastasis.

Topics: AC133 Antigen; Animals; Carcinogenesis; Carrier Proteins; Cell Line, Tumor; Cell Movement; Colonic Neoplasms; Disease Models, Animal; Fatty Acids; GTP-Binding Proteins; Isografts; Linoleic Acid; Male; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Nuclear Proteins; Oleic Acid; Oleic Acids; RNA-Binding Proteins; Stromal Cells

The present study aimed to evaluate the impact of Raphanus sativus cv Sango sprout juice (SSJ) administration (75mg/kg b.w. SSJ/day) on the brain lipidomic profile (fatty acid, sterols, cholesterol oxidation) of rats (non-genetic model) subjected to a high-fat (34% crude fat) dietary regimen. The SSJ did not affect the lipid infiltration (7.7-9.3%) and the fatty acid composition of the rat brain, which was mainly composed by unsaturated fatty acids (∼58%); however, the high-fat diet regimen significantly halved linoleic acid (LA). The high-fat diet also decreased (21.13mg/g) the level of brain cholesterol with respect to the regular diet (4.5% crude fat) (23.83mg/g); however, when the diet was shifted from high-fat to a regular regimen with or without SSJ supplementation, the levels of cholesterol significantly (p <0.05) increased up to 30.46mg/g of brain. The main oxysterols were 24(S)-hydroxycholesterol (24(S)-HC) and β-epoxycholesterol (β-EC). The high-fat diet led to the highest cholesterol oxidation (63.1μg/g), increasing 27-hydroxycholesterol (27-HC) infiltration (0.24μg/g rat brain) through the blood-brain barrier (BBB) compared to the regular diet (0.13μg/g rat brain). On the other hand, when the diet was switched from high-fat to a regular regimen with SSJ supplementation, a significant reduction of 27-HC in the rat brain was found. Although 24-HC did not significantly change (p=0.054), an increasing trend was observed when high-fat diet was supplied. The principal component analysis (PCA) revealed that SSJ was more active in counteracting cholesterol oxidation when supplied with the high-fat diet, due to inverse correlation with 24(S)-HC and 27-HC; however, further studies are needed to better understand which is the relationship between LA and cholesterol homeostasis in rat brain.

Topics: Animals; Brain; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fruit and Vegetable Juices; Linoleic Acid; Lipids; Male; Obesity; Oxysterols; Principal Component Analysis; Raphanus; Rats; Rats, Sprague-Dawley

Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Disease Models, Animal; Drug Resistance; Epithelial Cells; Humans; Hypersensitivity; Linoleic Acid; Lipid Metabolism; Mice; NF-kappa B; Receptors, Glucocorticoid; Respiratory Mucosa; Steroids

Hair loss (alopecia) is a universal problem for numerous people in the world. The present study was conducted to investigate the effects of red ginseng oil (RGO) and its major components on hair re-growth using testosterone (TES)-induced delay of anagen entry in C57BL/6 mice and their mechanisms of action. Seven-week-old C57BL/6 mice were daily treated with TES for 1 h prior to topical application of 10% RGO, 1% linoleic acid (LA), 1% β-sitosterol (SITOS), or 1% bicyclo(10.1.0)tridec-1-ene (BICYCLO) once a day for 28 days. Hair regenerative capacity was significantly restored by treatment of RGO and its major compounds in the TES-treated mice. Histological analysis showed that RGO along with LA and SITOS but not BICYCLO promoted hair growth through early inducing anagen phase that was delayed by TES in mice. Treatment of mice with RGO, LA, or SITOS up-regulated Wnt/β-catenin and Shh/Gli pathways-mediated expression of genes such as β-catenin, Lef-1, Sonic hedgehog, Smoothened, Gli-1, Cyclin D1, and Cyclin E in the TES-treated mice. In addition, RGO and its major components reduced the protein level of TGF-β but enhanced the expression of anti-apoptotic protein Bcl-2. These results suggest that RGO is a potent novel therapeutic natural product for treatment of androgenic alopecia possibly through hair re-growth activity of its major components such as LA and SITOS.

Topics: Alopecia; Animals; beta Catenin; Cyclins; Disease Models, Animal; Gene Expression Regulation; Hair Follicle; Hedgehog Proteins; Linoleic Acid; Lymphoid Enhancer-Binding Factor 1; Male; Mice; Mice, Inbred C57BL; Panax; Plant Oils; Proto-Oncogene Proteins c-bcl-2; Regeneration; Sitosterols; Smoothened Receptor; Testosterone; Transforming Growth Factor beta; Zinc Finger Protein GLI1

Alcoholic liver disease is a major human health problem leading to significant morbidity and mortality in the United States and worldwide. Dietary fat plays an important role in alcoholic liver disease pathogenesis. Herein, we tested the hypothesis that a combination of ethanol and a diet rich in linoleic acid (LA) leads to the increased production of oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxyoctadecadienoic acids (HODEs), which contribute to a hepatic proinflammatory response exacerbating liver injury. Mice were fed unsaturated (with a high LA content) or saturated fat diets (USF and SF, respectively) with or without ethanol for 10 days, followed by a single binge of ethanol. Compared to SF+ethanol, mice fed USF+ethanol had elevated plasma alanine transaminase levels, enhanced hepatic steatosis, oxidative stress, and inflammation. Plasma and liver levels of 9- and 13-HODEs were increased in response to USF+ethanol feeding. We demonstrated that primarily 9-HODE, but not 13-HODE, induced the expression of several proinflammatory cytokines in vitro in RAW264.7 macrophages. Finally, deficiency of arachidonate 15-lipoxygenase, a major enzyme involved in LA oxidation and OXLAM production, attenuated liver injury and inflammation caused by USF+ethanol feeding but had no effect on hepatic steatosis. This study demonstrates that OXLAM-mediated induction of a proinflammatory response in macrophages is one of the potential mechanisms underlying the progression from alcohol-induced steatosis to alcoholic steatohepatitis.

Topics: Animals; Arachidonate 15-Lipoxygenase; Binge Drinking; Body Composition; Cytokines; Dietary Fats; Disease Models, Animal; Ethanol; Inflammation; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Liver; Macrophages; Metabolome; Mice; Mice, Inbred C57BL; Oxidation-Reduction; Oxidative Stress; RAW 264.7 Cells

Polycystic ovary syndrome (PCOS) is a complex syndrome showing clinical features of an endocrine/metabolic disorder, including hyperinsulinemia and hyperandrogenism. Polyunsaturated fatty acids (PUFAs) and their derivatives, both tightly linked to PCOS and obesity, play important roles in inflammation and reproduction.. This study aimed to investigate serum lipid profiles in newly diagnosed patients with PCOS using lipidomics and correlate these features with the hyperinsulinemia and hyperandrogenism associated with PCOS and obesity.. Thirty-two newly diagnosed women with PCOS and 34 controls were divided into obese and lean subgroups. A PCOS rat model was used to validate results of the human studies.. Serum lipid profiles, including phospholipids, free fatty acids (FFAs), and bioactive lipids, were analyzed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS.. Elevation in phosphatidylcholine and a concomitant decrease in lysophospholipid were found in obese patients with PCOS vs lean controls. Obese patients with PCOS had decreased PUFA levels and increased levels of long-chain saturated fatty acids vs lean controls. Serum bioactive lipids downstream of arachidonic acid were increased in obese controls, but reduced in both obese and lean patients with PCOS vs their respective controls.. Patients with PCOS showed abnormal levels of phosphatidylcholine, FFAs, and PUFA metabolites. Circulating insulin and androgens may have opposing effects on lipid profiles in patients with PCOS, particularly on the bioactive lipid metabolites derived from PUFAs. These clinical observations warrant further studies of the molecular mechanisms and clinical implications of PCOS and obesity.

Topics: Adult; Androgens; Animals; Arachidonic Acid; Blood Glucose; Case-Control Studies; Ceramides; Cholesterol, HDL; Cholesterol, LDL; Chromatography, Liquid; Dehydroepiandrosterone Sulfate; Diet, High-Fat; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Humans; Hyperandrogenism; Hyperinsulinism; Insulin; Linoleic Acid; Lipid Metabolism; Mass Spectrometry; Obesity; Phosphatidic Acids; Phosphatidylglycerols; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Sex Hormone-Binding Globulin; Testosterone; Triglycerides; Young Adult

The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties.. This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model.. The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages.. Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.

Topics: Animals; Antioxidants; CD4-Positive T-Lymphocytes; Curcumin; Diet, High-Fat; Disease Models, Animal; Fatty Liver; Hepatocytes; Humans; Leptin; Linoleic Acid; Liver; Mice; Non-alcoholic Fatty Liver Disease; Reactive Oxygen Species

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Case-Control Studies; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Choline; Diet; Disease Models, Animal; Genes, myc; Hepatocytes; Humans; Linoleic Acid; Lipid Metabolism; Liver; Liver Neoplasms; Male; Methionine; Mice; Mice, Inbred C57BL; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Reactive Oxygen Species

Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.

Topics: Animals; Binge Drinking; Caspase 3; Chemokine CCL2; Chemokine CXCL2; Disease Models, Animal; Ethanol; Hep G2 Cells; Humans; Inflammation; Interleukin-6; Ligands; Linoleic Acid; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; TRPV Cation Channels; Tumor Necrosis Factor-alpha

The CD1-pcy/pcy mouse model of nephronophthisis displays reduced renal docosahexaenoic acid (DHA) levels and alterations in renal cyclooxygenase and lipoxygenase oxylipins derived from n-6 fatty acids. Since dietary flax oil ameliorates disease progression, its effect on renal fatty acids and oxylipins was examined. Sixteen weeks of feeding resulted in reduced disease progression and enrichment of renal phospholipid α-linolenic acid (ALA) and eicosapentaenoic acid, reduction in arachidonic acid (AA), but no change in linoleic acid (LA) or DHA. In diseased kidneys, flax oil feeding mitigated the elevated levels of renal cyclooxygenase derived oxylipins formed from AA and the lowered lipoxygenase and cytochrome P450 derived oxylipins formed from ALA and DHA. Increased DHA oxylipins occurred with flax feeding despite not altering DHA levels. Dietary flax oil may therefore reduce disease progression via mitigation of oxylipin abnormalities. This study also provides evidence of in vivo ALA conversion to DHA in amounts necessary to restore DHA oxylipin levels.

Topics: Animals; Disease Models, Animal; Docosahexaenoic Acids; Kidney; Kidney Diseases, Cystic; Linoleic Acid; Linseed Oil; Male; Mice; Oxylipins; Prostaglandin-Endoperoxide Synthases; Treatment Outcome; TRPP Cation Channels

Exposure to rotenone in vivo results in selective degeneration of dopaminergic neurons and development of neuropathologic features of Parkinson's disease (PD). As rotenone acts as an inhibitor of mitochondrial respiratory complex I, we employed oxidative lipidomics to assess oxidative metabolism of a mitochondria-specific phospholipid, cardiolipin (CL), in substantia nigra (SN) of exposed animals. We found a significant reduction in oxidizable polyunsaturated fatty acid (PUFA)-containing CL molecular species. We further revealed increased contents of mono-oxygenated CL species at late stages of the exposure. Notably, linoleic acid in sn-1 position was the major oxidation substrate yielding its mono-hydroxy- and epoxy-derivatives whereas more readily "oxidizable" fatty acid residues (arachidonic and docosahexaenoic acids) remained non-oxidized. Elevated levels of PUFA CLs were detected in plasma of rats exposed to rotenone. Characterization of oxidatively modified CL molecular species in SN and detection of PUFA-containing CL species in plasma may contribute to better understanding of the PD pathogenesis and lead to the development of new biomarkers of mitochondrial dysfunction associated with this disease.

Topics: Animals; Arachidonic Acid; Biomarkers; Cardiolipins; Chromatography, High Pressure Liquid; Disease Models, Animal; Docosahexaenoic Acids; Linoleic Acid; Male; Mass Spectrometry; Mitochondria; Oxidation-Reduction; Parkinsonian Disorders; Rats, Inbred Lew; Rotenone; Substantia Nigra; Time Factors

The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma.. BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry.. TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05).. This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cyclooxygenase Inhibitors; Diet; Disease Models, Animal; Drug Synergism; Fatty Acids, Omega-3; Female; Juglans; Linoleic Acid; Lipoxygenase; Male; Melatonin; Mice, Inbred BALB C; Nuts; Phytotherapy; Prostaglandin-Endoperoxide Synthases

Previous studies on rats and human subjects have established that the linoleic acid (LA) requirement is 2 % of the total energy intake (en%), but is obtained in the absence of α-linolenic acid (ALA) and consequently appear to be overestimated. This raises questions since a recent study including ALA has suggested to divide the historical value by four. However, this recent study has remained inconclusive because the animals used were not totally LA-deficient animals. For the first time, the present study was especially designed using physiological and biochemical markers and performed in two steps: (1) to achieve a specific n-6 fatty acid deficiency model using growing male rats fed either a 0 en% from LA/0 en% from ALA (0LA/0ALA), 0LA/0·5ALA or 2LA/0·5ALA diet, born from female rats fed a 0LA/0·5ALA diet; and (2) to refine the required level of LA in the presence of ALA using rats fed either a 0LA/0ALA, 0·5LA/0·5ALA, 1LA/0·5ALA, 1·5LA/0·5ALA diet, born from female rats fed a 0LA/0·5ALA diet. The first step shows that the best LA deficiency model was obtained using rats fed the 0LA/0ALA diet, born from female rats fed the 0LA/0·5ALA diet. The second step demonstrates that in growing rats, LA deficiency was corrected with an intake of 1-1·5 en% from LA and 0·5 en% from ALA. These data suggest that the requirements in humans should be revisited, considering the presence of ALA to set up the recommendation for LA.

Topics: alpha-Linolenic Acid; Animals; Biomarkers; Deficiency Diseases; Disease Models, Animal; Energy Intake; Female; Fetal Development; Lactation; Linoleic Acid; Male; Maternal Nutritional Physiological Phenomena; Nutritional Requirements; Pregnancy; Random Allocation; Rats, Wistar; Skin Diseases, Metabolic; Tail; Weaning; Weight Gain

Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

Topics: Animals; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Colitis; Colorectal Neoplasms; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fruit; Gene Expression Regulation; Inflammation Mediators; Linoleic Acid; Linolenic Acids; Lipopolysaccharides; Macrophages; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Morus; Mucin-2; NF-kappa B; Nitric Oxide; Phosphorylation; Plant Extracts; Protein Transport; Signal Transduction

It is important to increase our understanding of gustatory detection of dietary fat and its contribution to fat preference. We studied the roles of the fat taste receptors CD36 and GPR120 and their interactions via Ca(2+) signaling in fungiform taste bud cells (TBC).. We measured Ca(2+) signaling in human TBC, transfected with small interfering RNAs against messenger RNAs encoding CD36 and GPR120 (or control small interfering RNAs). We also studied Ca(2+) signaling in TBC from CD36(-/-) mice and from wild-type lean and obese mice. Additional studies were conducted with mouse enteroendocrine cell line STC-1 that express GPR120 and stably transfected with human CD36. We measured release of serotonin and glucagon-like peptide-1 from human and mice TBC in response to CD36 and GPR120 activation.. High concentrations of linoleic acid induced Ca(2+) signaling via CD36 and GPR120 in human and mice TBC, as well as in STC-1 cells, and low concentrations induced Ca(2+) signaling via only CD36. Incubation of human and mice fungiform TBC with lineoleic acid down-regulated CD36 and up-regulated GPR120 in membrane lipid rafts. Obese mice had decreased spontaneous preference for fat. Fungiform TBC from obese mice had reduced Ca(2+) and serotonin responses, but increased release of glucagon-like peptide-1, along with reduced levels of CD36 and increased levels of GPR120 in lipid rafts.. CD36 and GPR120 have nonoverlapping roles in TBC signaling during orogustatory perception of dietary lipids; these are differentially regulated by obesity.

Topics: Animals; Behavior, Animal; Calcium Signaling; CD36 Antigens; Cell Line; Diet, High-Fat; Disease Models, Animal; Food Preferences; Glucagon-Like Peptide 1; Humans; Inositol 1,4,5-Trisphosphate; Linoleic Acid; Membrane Microdomains; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Receptors, G-Protein-Coupled; RNA Interference; Serotonin; Taste; Taste Buds; Taste Perception; Transfection

Lipocalin-2 is a proinflammatory adipokine upregulated in obese humans and animals. A pathogenic role of lipocalin-2 in hypertension has been suggested. Mice lacking lipocalin-2 are protected from dietary obesity-induced cardiovascular dysfunctions. Administration of lipocalin-2 causes abnormal vasodilator responses in mice on a high-fat diet (HFD).. Wild-type and lipocalin-2 knockout mice were fed with standard chow or HFD. Immunoassays were performed for evaluating the circulating and tissue contents of lipocalin-2. The relaxation and contraction of arteries were studied using a wire myograph. Blood pressure was monitored with implantable radio telemetry. Dietary obesity promoted the accumulation of lipocalin-2 protein in blood and arteries. Deficiency of this adipokine protected mice from dietary obesity-induced elevation of blood pressure. Mass spectrometry analysis revealed that human and murine lipocalin-2 were modified by polyamination. Polyaminated lipocalin-2 was rapidly cleared from the circulation. Adipose tissue was a major site for lipocalin-2 deamidation. The circulating levels and the arterial accumulation of deamidated lipocalin-2 were significantly enhanced by treatment with linoleic acid (18:2n-6), which bound to lipocalin-2 with high affinity and prevented its interactions with matrix metalloproteinase 9 (MMP9). Combined administration of linoleic acid with lipocalin-2 caused vascular inflammation and endothelial dysfunction and raised the blood pressure of mice receiving standard chow. A human lipocalin-2 mutant with cysteine 87 replaced by alanine (C87A) contained less polyamines and exhibited a reduced capacity to form heterodimeric complexes with MMP9. After treatment, C87A remained in the circulation for a prolonged period of time and evoked endothelial dysfunction in the absence of linoleic acid.. Polyamination facilitates the clearance of lipocalin-2, whereas the accumulation of deamidated lipocalin-2 in arteries causes vascular inflammation, endothelial dysfunction, and hypertension.

Topics: Acute-Phase Proteins; Adipose Tissue; Animals; Aorta; Blood Pressure; Deamination; Diet, High-Fat; Disease Models, Animal; Endothelium, Vascular; Humans; Hypertension; Linoleic Acid; Lipocalin-2; Lipocalins; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Obesity; Oncogene Proteins; Proto-Oncogene Proteins; Time Factors; Vasodilation

Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n-6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFα, IL-1β and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Dietary Fats; Disease Models, Animal; Fatty Acids, Omega-3; Interleukin-1beta; Intestinal Mucosa; Linoleic Acid; Male; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

To comparatively investigate the effects of linoleic acid on convulsive and nonconvulsive epileptic seizures.. Rats were divided into 3 groups: convulsive epileptic rats receiving only pentylentetrazole (PTZ) injections (group 1), convulsive epileptic rats receiving PTZ and linoleic acid (group 2), and Wistar Albino Glaxo rats from Rijswijk with genetic absence epilepsy receiving linoleic acid (group 3). The duration and severity of convulsive activity were determined in groups in which convulsive seizures were induced by PTZ. In group 3, intravenous linoleic acid was administered after 1-h baseline electroencephalography (EEG) recordings. The EEG recordings were analyzed.. When groups 1 and 2 were compared, the delay in onset of minor seizures and the decrease in the number of rats developing major seizures were found statistically significant. When the mean spike-wave discharge number and duration values for the rats in group 3 were compared to baseline values, a statistically significant increase was found in the 1st and 6th hours and there was no significant difference in the 24th hour.. While our study shows that linoleic acid may be effective in the treatment of generalized convulsive epilepsy along with conventional antiepileptic drugs used in epilepsy treatment, it reports that linoleic acid is not appropriate in the treatment of nonconvulsive epilepsies.

Topics: Animals; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Epilepsy, Tonic-Clonic; Linoleic Acid; Pentylenetetrazole; Rats, Wistar

Airway epithelial injury is the hallmark of various respiratory diseases, but its mechanisms remain poorly understood. While 13-S-hydroxyoctadecadienoic acid (13-S-HODE) is produced in high concentration during mitochondrial degradation in reticulocytes little is known about its role in asthma pathogenesis. Here, we show that extracellular 13-S-HODE induces mitochondrial dysfunction and airway epithelial apoptosis. This is associated with features of severe airway obstruction, lung remodeling, increase in epithelial stress related proinflammatory cytokines and drastic airway neutrophilia in mouse. Further, 13-S-HODE induced features are attenuated by inhibiting Transient Receptor Potential Cation Channel, Vanilloid-type 1 (TRPV1) both in mouse model and human bronchial epithelial cells. These findings are relevant to human asthma, as 13-S-HODE levels are increased in human asthmatic airways. Blocking of 13-S-HODE activity or disruption of TRPV1 activity attenuated airway injury and asthma mimicking features in murine allergic airway inflammation. These findings indicate that 13-S-HODE induces mitochondrial dysfunction and airway epithelial injury.

Topics: Animals; Asthma; Calcium; Disease Models, Animal; Extracellular Space; Fatty Acids, Unsaturated; Gene Knockdown Techniques; Humans; Linoleic Acid; Mice; Mice, Inbred BALB C; Mitochondria; Neutrophils; Respiratory Mucosa; Species Specificity; TRPV Cation Channels

A growing body of evidence suggests that mitochondrial proton-leak functions as a regulator of reactive oxygen species production and its modulation may limit oxidative injury to tissues. The main purpose of this work was to characterize the proton-leak of brain cortical mitochondria from long-term hyperglycemic and insulin-induced recurrent hypoglycemic rats through the modulation of the uncoupling protein 2 (UCP2) and adenine nucleotide translocator (ANT). Streptozotocin-induced diabetic rats were treated subcutaneously with twice-daily insulin injections during 2 weeks to induce the hypoglycemic episodes. No differences in the basal proton-leak, UCP2 and ANT protein levels were observed between the experimental groups. Mitochondria from recurrent hypoglycemic rats presented a decrease in proton-leak in the presence of GDP, a specific UCP2 inhibitor, while an increase in proton-leak was observed in the presence of linoleic acid, a proton-leak activator, this effect being reverted by the simultaneous addition of GDP. Mitochondria from long-term hyperglycemic rats showed an enhanced susceptibility to ANT modulation as demonstrated by the complete inhibition of basal and linoleic acid-induced proton-leak caused by the ANT specific inhibitor carboxyatractyloside. Our results show that recurrent-hypoglycemia renders mitochondria more susceptible to UCPs modulation while the proton-leak of long-term hyperglycemic rats is mainly modulated by ANT, which suggest that brain cortical mitochondria have distinct adaptation mechanisms in face of different metabolic insults.

Topics: Animals; Brain; Diabetes Mellitus, Experimental; Disease Models, Animal; Hyperglycemia; Hypoglycemia; Ion Channels; Linoleic Acid; Male; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial ADP, ATP Translocases; Mitochondrial Proteins; Rats; Rats, Wistar; Uncoupling Protein 2

Hairless mice fed a special diet, HR-AD, develop atopic dermatitis (AD)-like skin inflammation with skin barrier defects and itch-related scratching; however, the ingredient(s) causing the dermatitis remains unclear. In this study, we examined whether deficiency of certain polyunsaturated fatty acids (PUFAs) is involved in HR-AD-induced AD. High-purity PUFAs were given to HR-AD-fed mice by dietary supplementation or gavage. Fatty acid levels in the serum and skin were determined by using gas chromatography-mass spectrometry. In serum from HR-AD-fed mice, linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), as well as their metabolites, were markedly decreased. When mice were fed HR-AD supplemented with LA or ALA in an amount equal to that contained in a normal diet, the development of AD-like symptoms was completely prevented by supplementation with LA but not with ALA. Relatively high dose of ALA slightly alleviated skin barrier defects, but did neither itch-related scratching nor skin inflammation. On the other hand, gavage administration of LA metabolites, such as γ-linolenic acid and arachidonic acid (AA), significantly ameliorated established dermatitis without increasing LA in the serum and skin. Moreover, AA-induced amelioration of dermatitis was not affected by pharmacological blockade of 5-lipoxygenase (5-LOX) and cyclooxygenase (COX), suggesting no involvement of 5-LOX- or COX-mediated AA metabolites in the amelioration. In conclusion, our results indicate that deficiency of n-6 PUFAs is mainly responsible for AD-like symptoms by HR-AD feeding. Thus, this model could be useful for studying the pathomechanisms associated with deficiency of n-6 PUFAs in AD.

Topics: Animals; Arachidonic Acid; Dermatitis, Atopic; Diet; Dietary Fats, Unsaturated; Disease Models, Animal; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Linoleic Acid; Mice; Mice, Hairless; Pruritus; Skin

Ethanol is a dietary factor that dose-dependently increases breast cancer risk in women. We previously have shown that ethanol increases mammary epithelial density through increased branching after dietary exposure during puberty in CD2/F1 mice. To extend these studies to parous mice in a breast cancer model, we used a transgenic mouse model of human parity-associated breast cancer, the FVB-MMTV-Her2/Neu mouse, which overexpresses wildtype EGFR2, resulting in constitutive activation of growth signaling in the mammary epithelium. Here we describe the short-term effects of ethanol feeding on progression through involution. Mice were fed diets supplemented with 0%, 0.5%, 1%, or 2% ethanol for 4, 9, or 14 d starting on day 21 of lactation (that is, at the start of natural postlactational involution). Unlike peripubertal mice exposed to ethanol, postlactational dams showed no changes in body weight; liver, spleen, and kidney weights; and pathology. Ethanol exposure had no effect on mammary gland lobular density and adipocyte size throughout involution. Likewise, the infiltration of inflammatory cells and serum oxidized lipid species were unchanged by diet, suggesting that ethanol feeding had no effect on local inflammation (leukocyte infiltration) or systemic inflammation (oxidized lipids). In conclusion, ethanol exposure of parous dams had no effect on mammary gland structure or the regression of the lactating mammary gland to a resting state. The period of involution that follows natural lactation appears to be refractory to developmental effects of ethanol on mammary epithelium.

Topics: Adipocytes; Analysis of Variance; Animals; Body Weight; Breast Neoplasms; Chromatography, Liquid; Disease Models, Animal; Ethanol; Female; Kidney; Lactation; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Mammary Glands, Animal; Mass Spectrometry; Mice; Mice, Transgenic; Organ Size; Receptor, ErbB-2; Spleen; Time Factors

Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm).. Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.

Topics: Adult; Animals; Carcinoma, Hepatocellular; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Diethylnitrosamine; Disease Models, Animal; Glutathione Peroxidase; Hepatocytes; Humans; Interleukin-8; Linoleic Acid; Lipid Peroxides; Liver Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Rats; Rats, Inbred F344; Selenium; Transcription Factor AP-1; Vascular Endothelial Growth Factor A

Increasing prevalence of inflammatory bowel disease may be due to imbalance in the intake of n-6 and n-3 PUFA in the diet. This study investigates the impact of varying ratios of dietary linoleic acid (LA, 18 : 2n-6) to α-linolenic acid (ALA, 18 : 3n-3) on the inflammatory response in dextran sulphate sodium (DSS)-induced colitis. Weanling male Sprague-Dawley rats were divided into five groups: a non-colitic group with a LA:ALA ratio of 215 (CON-215), and colitic groups with LA:ALA ratios of 215 (DSS-215), 50 (DSS-50), 10 (DSS-10) and 2 (DSS-2). Blends of groundnut, palmolein and linseed oils were used to provide varying LA:ALA ratios. All the rats were fed the respective experimental isoenergetic diets containing 10 % fat for 90 d and DSS was administered during the last 11 d. Colonic inflammation was evaluated by clinical, biochemical and histological parameters. The results showed attenuation of colitis in the DSS-2 group as evidenced by significant reductions in disease activity index, mucosal myeloperoxidase activity (P < 0·05), alkaline phosphatase activity (P < 0·01) and increase in colon length (P < 0·01) compared to the groups fed with higher ratios (DSS-215). This was accompanied by significant reductions in mucosal proinflammatory cytokines TNF-α (P < 0·01) and IL-1β (P < 0·01) and improvement in the histological score. Further, ALA supplementation increased long-chain (LC) n-3 PUFA and decreased LC n-6 PUFA in colon structural lipids. These data suggest that substitution of one-third of LA with ALA (LA:ALA ratio 2) mitigates experimental colitis by down-regulating proinflammatory mediators.

Topics: alpha-Linolenic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Colitis; Colon; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Inflammatory Bowel Diseases; Intestinal Mucosa; Linoleic Acid; Male; Neutrophil Infiltration; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Weaning

It is important to evaluate the ability of novel proteins in food crops and products to elicit potentially harmful immunologic responses, including allergic hypersensitivity. We developed a novel mouse model of food allergy involving an oral challenge of a protein antigen after feeding of the antigen in combination with modulating factors often ingested in daily life, namely, dietary oil emulsion and salicylate. In the model, BALB/c mice were sensitized orally for three weeks with ovalbumin (OVA) in linoleic acid/lecithin emulsion, followed immediately by intraperitoneal injection of sodium salicylate. At the end of the sensitization, the incidence of mice positive for serum OVA-specific IgG1 but not IgE had significantly increased in the combined-sensitization group. After the 3-week sensitization, a single or double oral challenge with OVA effectively and significantly caused severe anaphylaxis, as compared with the groups sensitized with OVA in the emulsion or the vehicle alone. Moderate increase of plasma histamine and intestinal abnormality in histology was found only in the combined-sensitization group. Anaphylaxis symptoms in the sensitized mice were induced more by oral challenge than by intravenous challenge, suggesting a critical role for the mucosal system. This is the first model for successful induction of oral anaphylaxis in mice sensitized by feeding of food protein without adjuvant. It will be useful to elucidate the mechanism of food allergy and to detect modulating factors of oral allergy at sensitization using this model, which simulates real life conditions.

Topics: Administration, Oral; Allergens; Anaphylaxis; Animals; Disease Models, Animal; Emulsions; Female; Food Hypersensitivity; Immunoglobulin G; Intestine, Small; Lecithins; Linoleic Acid; Mice; Mice, Inbred BALB C; Ovalbumin; Salicylic Acid

Identification of molecular mechanisms underlying early stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, nontargeted metabonomics of TASTPM transgenic AD mice was performed. The metabolic profiles of both brain and plasma of TASTPM mice were characterized using gas chromatography-mass spectrometry and compared to those of wild-type C57BL/6J mice. TASTPM mice were metabolically distinct compared to wild-type mice (Q2Y=0.587 and 0.766 for PLS-DA models derived from brain and plasma, respectively). A number of metabolites were found to be perturbed in TASTPM mice in both brain (D-fructose, L-valine, L-serine, L-threonine, zymosterol) and plasma (D-glucose, D-galactose, linoleic acid, arachidonic acid, palmitic acid and D-gluconic acid). In addition, enzyme immunoassay confirmed that selected endogenous steroids were significantly perturbed in brain (androstenedione and 17-OH-progesterone) and plasma (cortisol and testosterone) of TASTPM mice. Ingenuity pathway analysis revealed that perturbations related to amino acid metabolism (brain), steroid biosynthesis (brain), linoleic acid metabolism (plasma) and energy metabolism (plasma) accounted for the differentiation of TASTPM and wild-type mice. Our results provided insights on the pathogenesis of APP-induced AD and reinforced the role of TASTPM in drug and biomarker development.

Topics: Alzheimer Disease; Amino Acids; Animals; Biomarkers; Brain; Carbohydrate Metabolism; Disease Models, Animal; Energy Metabolism; Gas Chromatography-Mass Spectrometry; Gluconates; Glucose; Hydrocortisone; Immunoenzyme Techniques; Linoleic Acid; Male; Metabolome; Metabolomics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Progesterone

In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω-3 fatty acids have been proposed as anti-inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto-Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of (14)C-triolein into adipose tissue was improved by the ω-3 administration. In vitro incubations of adipose tissue slices from EPA-treated rats showed an increase in (14)C-palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP-activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator-activated receptor-α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2-deoxy-D-[(14)C]glucose (2-DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear.

Topics: Adipose Tissue; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids; Humans; Inflammation; Insulin Resistance; Linoleic Acid; Lipid Metabolism; Male; Muscle, Skeletal; Rats

Fatty acid-binding proteins (FABPs) are postulated to serve as lipid shuttles that solubilize hydrophobic fatty acids and deliver them to appropriate intracellular sites. Epidermal FABP (E-FABP/FABP5) is predominantly expressed in keratinocytes and is overexpressed in the actively proliferating tissue characteristic of psoriasis and wound healing. In this study, we found decreased expression of the differentiation-specific proteins keratin 1, involucrin, and loricrin in E-FABP(-/-) keratinocytes relative to E-FABP(+/+) keratinocytes. We also determined that incorporation of linoleic acid was significantly reduced in E-FABP(-/-) keratinocytes. Although linoleic acid did not directly affect keratinocyte differentiation, keratin 1 expression was induced by the linoleic acid derivative 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE), and this induction was concomitant with increased NF-κB activity. In E-FABP(-/-) keratinocytes, the expression of 13(S)-HODE and the subsequent induction of NF-κB activity was lower than in wild-type keratinocytes. The reduction of linoleic acid in E-FABP(-/-) keratinocytes led to decreased cellular 13(S)-HODE content, resulting in decreased keratin 1 expression through downregulation of NF-κB activity. The regulation of fatty acid metabolism by E-FABP during keratinocyte differentiation suggests that E-FABP may have a role in the pathogenesis of psoriasis.

Topics: Animals; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Epidermis; Fatty Acid-Binding Proteins; Fatty Acids; Keratin-1; Keratinocytes; Linoleic Acid; Linoleic Acids; Membrane Proteins; Mice; Mice, Knockout; Neoplasm Proteins; NF-kappa B; Protein Precursors; Psoriasis; Signal Transduction

α-Lipoic acid (ALA) has been termed the 'ideal' antioxidant, a readily absorbed and bioavailable compound capable of scavenging a number of free radicals, and it has been used for treating diseases in which oxidative stress plays a major role. The present study was designed to gain a better understanding for the positive effects of ALA on the models of acute and chronic inflammation in rats, and also determine its anti-oxidative potency. In an acute model, three doses of ALA (50, 100 and 200 mg/kg) and one dose of indomethacin (25 mg/kg) or diclofenac (25 mg/kg) were administered to rats by oral administration. The paw volumes of the animals were calculated plethysmometrically, and 0·1 ml of 1 % carrageenan (CAR) was injected into the hind paw of each animal 1 h after oral drug administration. The change in paw volume was detected as five replicates every 60 min by plethysmometry. In particular, we investigated the activities of catalase, superoxide dismutase (SOD), glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), inducible NO synthase (iNOS) and myeloperoxidase (MPx), and the amounts of lipid peroxidation (LPO) or total GSH in the paw tissues of CAR-injected rats. We showed that ALA exhibited anti-inflammatory effects on both acute and chronic inflammations, and a strongly anti-oxidative potency on linoleic acid oxidation. Moreover, the administration of CAR induced oedema in the paws. ALA significantly inhibited the ability of CAR to induce: (1) the degree of acute inflammation, (2) the rise in MPx activity, (3) the increases of GST and iNOS activities and the amount of LPO and (4) the decreases of GPx, GR and SOD activities and the amount of GSH. In conclusion, these results suggest that the anti-inflammatory properties of ALA, which has a strong anti-oxidative potency, could be related to its positive effects on the antioxidant system in a variety of tissues in rats.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carrageenan; Cotton Fiber; Disease Models, Animal; Edema; Enzymes; Hindlimb; Inflammation; Linoleic Acid; Lipid Peroxidation; Male; Rats; Rats, Wistar; Thioctic Acid

Oxidative damage of membrane polyunsaturated fatty acids (PUFA) is thought to play a major role in mitochondrial dysfunction related to Parkinson's disease (PD). The toxic products formed by PUFA oxidation inflict further damage on cellular components and contribute to neuronal degeneration. Here, we tested the hypothesis that isotopic reinforcement, by deuteration of the bisallylic sites most susceptible to oxidation in PUFA may provide at least partial protection against nigrostriatal injury in a mouse model of oxidative stress and cell death, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Mice were fed a fat-free diet supplemented with saturated acids, oleic acid and essential PUFA: either normal, hydrogenated linoleic (LA, 18:2n-6) and α-linolenic (ALA, 18:3n-3) or deuterated 11,11-D2-LA and 11,11,14,14-D4-ALA in a ratio of 1:1 (to a total of 10% mass fat) for 6 days; each group was divided into two cohorts receiving either MPTP or saline and then continued on respective diets for 6 days. Brain homogenates from mice receiving deuterated PUFA (D-PUFA) vs. hydrogenated PUFA (H-PUFA) demonstrated a significant incorporation of deuterium as measured by isotope ratio mass-spectrometry. Following MPTP exposure, mice fed H-PUFA revealed 78.7% striatal dopamine (DA) depletion compared to a 46.8% reduction in the D-PUFA cohort (as compared to their respective saline-treated controls), indicating a significant improvement in DA concentration with D-PUFA. Similarly, higher levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected in MPTP-exposure mice administered D-PUFA; however, saline-treated mice revealed no change in DA or DOPAC levels. Western blot analyses of tyrosine hydroxylase (TH) confirmed neuroprotection with D-PUFA, as striatal homogenates showed higher levels of TH immunoreactivity in D-PUFA (88.5% control) vs. H-PUFA (50.4% control) in the MPTP-treated cohorts. In the substantia nigra, a significant improvement was noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; alpha-Linolenic Acid; Animals; Cell Death; Corpus Striatum; Deuterium; Disease Models, Animal; Fatty Acids, Unsaturated; Linoleic Acid; Mice; Mice, Inbred C57BL; Nerve Degeneration; Oleic Acid; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra

Acute inflammation is a common feature of many life-threatening pathologies, including septic shock. One hallmark of acute inflammation is the peroxidation of polyunsaturated fatty acids forming bioactive products that regulate inflammation. Myeloperoxidase (MPO) is an abundant phagocyte-derived hemoprotein released during phagocyte activation. Here, we investigated the role of MPO in modulating biologically active arachidonic acid (AA) and linoleic acid (LA) metabolites during acute inflammation. Wild-type and MPO-knockout (KO) mice were exposed to intraperitoneally injected endotoxin for 24 h, and plasma LA and AA oxidation products were comprehensively analyzed using a liquid chromatography-mass spectrometry method. Compared to wild-type mice, MPO-KO mice had significantly lower plasma levels of LA epoxides and corresponding LA- and AA-derived fatty acid diols. AA and LA hydroxy intermediates (hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids) were also significantly lower in MPO-KO mice. Conversely, MPO-deficient mice had significantly higher plasma levels of cysteinyl-leukotrienes with well-known proinflammatory properties. In vitro experiments revealed significantly lower amounts of AA and LA epoxides, LA- and AA-derived fatty acid diols, and AA and LA hydroxy intermediates in stimulated polymorphonuclear neutrophils isolated from MPO-KO mice. Our results demonstrate that MPO modulates the balance of pro- and anti-inflammatory lipid mediators during acute inflammation and, in this way, may control acute inflammatory diseases.

Topics: Animals; Arachidonic Acid; Chromatography, Liquid; Disease Models, Animal; Epoxy Compounds; Fatty Acids, Unsaturated; Hydroxyeicosatetraenoic Acids; Inflammation; Linoleic Acid; Lipopolysaccharides; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peroxidase; Shock, Septic

To investigate substance basis for improving pharmacodynamics by comparing the chemical constituents of petroleum ether extraction from crude and processed Cornus officinalis and the effects on the immunologic function of mice with immunosuppression induced.. The volatile components in petroleum ether extraction were analyses by GC-MS. Non-specific immune function was determined by cleaning carbon particle index K, Swallow index a, spleen index and thymus index. The specific humoral immune function was evaluated by detecting the content of serum hemolysin.. The chemical constituents of petroleum ether extraction of Cornus officinalis before and after being processed had significant changes. After being processed, Vitamin E increased by 46.6%, linoleic acid increased by 18.3% and methyl linen increased by 30.9%. The extraction increased clearance rate of charcoal carbon particles index K, swallow index alpha, spleen index, thymus index and the level of serum hemolysin.. The extraction can markedly improve non-specific immune function and the specific humoral immune function which are active sites of improving immunologic function and post-processed is better. Substance basis could be Vitamin E, Linoleic acid, methyl linen and so on.

Topics: Animals; Cornus; Cyclophosphamide; Disease Models, Animal; Female; Gas Chromatography-Mass Spectrometry; Hemolysin Proteins; Immunity; Immunosuppression Therapy; Linoleic Acid; Male; Mice; Organ Size; Phagocytosis; Plant Extracts; Plants, Medicinal; Random Allocation; Spleen; Vitamin E

Cystic fibrosis (CF) patients display a fatty acid imbalance characterized by low linoleic acid levels and variable changes in arachidonic acid. This led to the recommendation that CF patients consume a high-fat diet containing >6% linoleic acid. We hypothesized that increased conversion of linoleic acid to arachidonic acid in CF leads to increased levels of arachidonate-derived proinflammatory metabolites and that this process is exacerbated by increasing linoleic acid levels in the diet. To test this hypothesis, we determined the effect of linoleic acid supplementation on downstream proinflammatory biomarkers in two CF models: 1) in vitro cell culture model using 16HBE14o(-) sense [wild-type (WT)] and antisense (CF) human airway epithelial cells; and 2) in an in vivo model using cftr(-/-) transgenic mice. Fatty acids were analyzed by gas chromatography-mass spectrometry (GC/MS), and IL-8 and eicosanoids were measured by ELISA. Neutrophils were quantified in bronchoalveolar lavage fluid from knockout mice following linoleic acid supplementation and exposure to aerosolized Pseudomonas LPS. Linoleic acid supplementation increased arachidonic acid levels in CF but not WT cells. IL-8, PGE(2), and PGF(2α) secretion were increased in CF compared with WT cells, with a further increase following linoleic acid supplementation. cftr(-/-) Mice supplemented with 100 mg of linoleic acid had increased arachidonic acid levels in lung tissue associated with increased neutrophil infiltration into the airway compared with control mice. These findings support the hypothesis that increasing linoleic acid levels in the setting of loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to increased arachidonic acid levels and proinflammatory mediators.

Topics: Animals; Arachidonic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Line; Cystic Fibrosis; Dietary Supplements; Disease Models, Animal; Eicosanoids; Fatty Acids; Humans; Inflammation; Interleukin-8; Linoleic Acid; MAP Kinase Signaling System; Mice; Mice, Inbred CFTR; Mice, Knockout; Mice, Transgenic; Pseudomonas aeruginosa; Respiratory Mucosa

Topics: Adiposity; Animals; Dietary Fats; Dietary Sucrose; Disease Models, Animal; Fatty Liver; Linoleic Acid; Physical Conditioning, Animal; Rats

An imbalance in (n-6)/(n-3) PUFA has been reported in cystic fibrosis (CF) patients. Glycerophospholipids enriched in docosahexaenoic acid (GPL-DHA) have been shown to regulate the (n-6)/(n-3) fatty acid ratio in the elderly. Here, we tested the effect of GPL-DHA supplementation on PUFA status in F508del homozygous CF mice. GPL-DHA liposomes were administrated by gavage (60 mg DHA/kg daily, i.e. at maximum 1.4 mg DHA/d) to 1.5-mo-old CF mice (CF+DHA) and their corresponding wild-type (WT) homozygous littermates (WT+DHA) for 6 wk. The PUFA status of different tissues was determined by GC and compared with control groups (CF and WT). There was an alteration in the (n-6) PUFA pathway in several CF-target organs in CF compared with WT mice, as evidenced by a higher level of arachidonic acid (AA) in membrane phospholipids or whole tissue (21 and 39% in duodenum-jejunum, 32 and 38% in ileum, and 19 and 43% in pancreas). Elevated AA levels were associated with lower linoleic acid (LA) and higher dihomo-gamma-linolenic acid levels. No DHA deficiency was observed. GPL-DHA treatment resulted in different PUFA composition changes depending on the tissue (increase in LA, decrease in elevated AA, DHA increase, increase in (n-6)/(n-3) fatty acid ratio). However, the DHA/AA ratio consistently increased in all tissues in CF+DHA and WT+DHA mice. Our study demonstrates the effectiveness of an original oral DHA formulation in counter-balancing the abnormal (n-6) fatty acid metabolism in organs of CF mice when administrated at a low dose and highlights the potential of the use of GPL-DHA as nutritherapy for CF patients.

Topics: Animals; Arachidonic Acid; Cell Membrane; Cystic Fibrosis; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Glycerophospholipids; Humans; Intestinal Mucosa; Intestines; Linoleic Acid; Lipids; Lung; Mice; Mice, Inbred Strains; Pancreas; Phospholipids; Sequence Deletion

Hyperlipidemia is the major risk factors of heart disease such as atherosclerosis, stroke, and death. In the present study, we studied the effect of gallic acid (GA), linoleic acid (LA), mixture of GA and LA (MGL), and chemically synthesized gallic acid-linoleic acid ester (octadeca-9,12-dienyl-3,4,5-trihydroxybenzoate, GLE) on the ability to ameliorate hyperlipidemia in C57BL/6 mice fed a high-fat diet (HFD). GLE, GA, LA, and MGL were mixed with HFD and the composition of the test compounds were 1% of the diet for 7 weeks. After 7 weeks, the average body weight of ND and GLE groups was lower than that of HFD group (P<0.05). The liver weight of mice decreased (P<0.05) in all treatment groups relative to HFD fed group. The plasma lipids such as triglyceride and LDL-cholesterol were found to be decreased (P<0.05) in GLE, GA, LA, and MGL fed mice when compared to that of HFD fed mice. But high-density lipoprotein (HDL) cholesterol increased (P<0.05) in HFD and GLE fed mice when compared to that of ND fed mice. The hepatic accumulation of fat droplets of GA, LA, GLE, and MGL group showed considerably lower than that of HFD group. Adipose histology showed that GLE supplementation was found to be more effective in decreasing the size of adipocyte relative to those of other treatment groups. In conclusion, the supplementation of synthetic GLE from gallic acid and linoleic acid ester may have a potential hypolipidemic effect on mice fed high-fat diet. Further studies are required to prove GLE as a hypolipidemic agent.

Topics: Adipocytes; Adipose Tissue; Animals; Body Weight; Cell Nucleus; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats; Disease Models, Animal; Fatty Liver; Female; Gallic Acid; Hyperlipidemias; Hypolipidemic Agents; Linoleic Acid; Lipids; Liver; Mice; Mice, Inbred C57BL; Obesity; Triglycerides

Recent studies indicate that high-fat diets may attenuate cardiac hypertrophy and contractile dysfunction in chronic hypertension. However, it is unclear whether consuming a high-fat diet improves prognosis in aged individuals with advanced hypertensive heart disease or the extent to which differences in its fatty acid composition modulate its effects in this setting. In this study, aged spontaneously hypertensive heart failure rats were administered a standard high-carbohydrate diet or high-fat diet (42% of kilocalories) supplemented with high-linoleate safflower oil or lard until death to determine their effects on disease progression and mortality. Both high-fat diets attenuated cardiac hypertrophy, left ventricular chamber dilation, and systolic dysfunction observed in rats consuming the high-carbohydrate diet. However, the lard diet significantly hastened heart failure mortality compared with the high-carbohydrate diet, whereas the linoleate diet significantly delayed mortality. Both high-fat diets elicited changes in the myocardial fatty acid profile, but neither had any effect on thromboxane excretion or blood pressure. The prosurvival effect of the linoleate diet was associated with a greater myocardial content and linoleate-enrichment of cardiolipin, an essential mitochondrial phospholipid known to be deficient in the failing heart. This study demonstrates that, despite having favorable effects on cardiac morphology and function in hypertension, a high-fat diet may accelerate or attenuate mortality in advanced hypertensive heart disease depending on its fatty acid composition. The precise mechanisms responsible for the divergent effects of the lard and linoleate-enriched diets merit further investigation but may involve diet-induced changes in the content and/or composition of cardiolipin in the heart.

Topics: Animal Feed; Animals; Blood Pressure; Cardiolipins; Diet, Fat-Restricted; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Echocardiography; Fatty Acids; Heart Failure; Hypertension; Kaplan-Meier Estimate; Linoleic Acid; Male; Myocardium; Rats; Rats, Mutant Strains; Thromboxanes

To study the efficacy of topical application of alpha-linolenic acid (ALA) and linoleic acid (LA) for dry eye treatment.. Formulations containing ALA, LA, combined ALA and LA, or vehicle alone, were applied to dry eyes induced in mice. Corneal fluorescein staining and the number and maturation of corneal CD11b(+) cells were determined by a masked observer in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva.. Dry eye induction significantly increased corneal fluorescein staining; CD11b(+) cell number and major histocompatibility complex Class II expression; corneal IL-1alpha and tumor necrosis factor alpha (TNF-alpha) expression; and conjunctival IL-1alpha, TNF-alpha, interferon gamma, IL-2, IL-6, and IL-10 expression. Treatment with ALA significantly decreased corneal fluorescein staining compared with both vehicle and untreated controls. Additionally, ALA treatment was associated with a significant decrease in CD11b(+) cell number, expression of corneal IL-1alpha and TNF-alpha, and conjunctival TNF-alpha.. Topical ALA treatment led to a significant decrease in dry eye signs and inflammatory changes at both cellular and molecular levels.. Topical application of ALA omega-3 fatty acid may be a novel therapy to treat the clinical signs and inflammatory changes accompanying dry eye syndrome.

Topics: Administration, Topical; alpha-Linolenic Acid; Animals; CD11b Antigen; Cell Count; Conjunctiva; Cornea; Cytokines; Disease Models, Animal; Dry Eye Syndromes; Fluorescein; Fluorescent Antibody Technique, Indirect; Linoleic Acid; Mice; Mice, Inbred C57BL; Monocytes; Ophthalmic Solutions; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome

Dietary n-3 fatty acids generally attenuate elevated cyclooxygenase-2 (COX-2) levels in disease states. However, models of renal cystic disease (RCD) exhibit reduced renal COX-2 expression. Therefore, the in vivo regulation of COX-2 expression by dietary n-3 fatty acids was examined. In archived tissues from dietary studies, COX-2 protein and gene expression was up-regulated in diseased pcy mouse and Han:SPRD-cy rat kidneys when given diets containing eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), but not those containing alpha-linolenic acid (ALA), compared to control diets with linoleic acid (LA). The presence of disease was necessary to elicit these effects as COX-2 expression was unaltered by diet in normal kidneys. The effects were specific for COX-2, since COX-1 levels were unaltered by these dietary manipulations in either model. Thus, in RCD, diets containing EPA and DHA but not ALA appear to specifically up-regulate renal COX-2 gene and protein levels in vivo.

Topics: Animals; Cyclooxygenase 2; Dietary Fats; Disease Models, Animal; Fatty Acids, Omega-3; Gene Expression Regulation, Enzymologic; Linoleic Acid; Male; Mice; Mice, Inbred Strains; Polycystic Kidney Diseases; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Weaning

To investigate the role of eicosapentaenoic acid (EPA), the major omega-3 polyunsaturated fatty acid (PUFA), in the development of choroidal neovascularization (CNV), together with underlying molecular mechanisms.. Six-week-old C57BL/6 mice were fed with laboratory chow with 5% EPA or the omega-6 PUFA linoleic acid (LA) for 4 weeks. Laser photocoagulation was performed to induce CNV, and the volume of CNV tissue was evaluated by volumetric measurements. The expression and production of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 in the retinal pigment epithelium (RPE)-choroid in vivo, and stimulated b-End3 endothelial cells and RAW264.7 macrophages in vitro were evaluated by RT-PCR and ELISA. Fatty acid composition in the serum and the RPE-choroid was analyzed by gas chromatography and high-performance liquid chromatography, respectively. Serum levels of C-reactive protein (CRP), IL-6, VEGF, MCP-1, and soluble ICAM-1 were examined by ELISA.. The CNV volume in EPA-fed animals was significantly suppressed compared with that in control mice, whereas the LA-rich diet did not affect CNV. The mRNA expression and protein levels of ICAM-1, MCP-1, VEGF, and IL-6 after CNV induction were significantly reduced in EPA-supplemented mice. In vitro, EPA application led to significant inhibition of mRNA and protein levels of ICAM-1 and MCP-1 in endothelial cells and VEGF and IL-6 in macrophages. EPA-fed mice exhibited significantly higher levels of EPA and lower levels of the omega-6 PUFA arachidonic acid in the serum and the RPE-choroid than control animals. EPA supplementation also led to significant reduction of serum levels of IL-6 and CRP after CNV induction.. The present study demonstrates for the first time that an EPA-rich diet results in significant suppression of CNV and CNV-related inflammatory molecules in vivo and in vitro. These results suggest that frequent consumption of omega-3 PUFAs may prevent CNV and lower the risk of blindness due to age-related macular degeneration.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Choroid; Choroidal Neovascularization; Chromatography, Gas; Chromatography, High Pressure Liquid; Diet; Disease Models, Animal; Eicosapentaenoic Acid; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fatty Acids; Intercellular Adhesion Molecule-1; Interleukin-6; Laser Coagulation; Linoleic Acid; Macrophages; Mice; Mice, Inbred C57BL; Pigment Epithelium of Eye; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A

In the water-maze test, the linoleic acid derivative, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (1 mg/kg, intraperitoneally), significantly shortened the prolonged latency for accelerated-senescence-prone mice 8 (SAMP8), reaching a level similar to the latency for accelerated-senescence-resistant mice 1 (SAMR1) as control. In the open-field test to assess motor activity, it was confirmed that the DCP-LA effect is not due to increased motor activity. In the passive avoidance test to assess fear memory, DCP-LA had no effect on the latency of acquisition and retention for SAMP8. The results of the present study, thus, suggest that DCP-LA could improve age-related learning impairment by enhancing cognitive functions.

Topics: Aging; Animals; Avoidance Learning; Behavior, Animal; Caprylates; Disease Models, Animal; Exploratory Behavior; Learning Disabilities; Linoleic Acid; Male; Maze Learning; Mice; Mice, Neurologic Mutants; Motor Activity; Reaction Time

Polyunsaturated fatty acids (PUFAs), including linoleic acid (C18 : 2) and alpha-linolenic acid (C18 : 3), are major components of membranes. PUFAs are produced from monounsaturated fatty acids by several fatty acid desaturases (FADs) in many fungi, but Saccharomyces cerevisiae, Schizosaccharomyces pombe and humans do not have these enzymes. Although the fungal pathogen Candida albicans produces C18 : 2 and C18 : 3, the enzymes that synthesize them have not yet been investigated. In this report, two ORFs, CaFAD2 and CaFAD3, were identified based on their homology to other yeast FADs, and CaFAD2 and CaFAD3 gene disruptants were constructed. Cafad2Delta and Cafad3Delta lost their ability to produce C18 : 2 and C18 : 3, respectively. Furthermore, S. cerevisiae cells expressing CaFad2p converted palmitoleic acid (C16 : 1) and C18 : 1 to hexadecadienoic acid (C16 : 2) and C18 : 2, respectively, and CaFad3p-expressing cells converted C18 : 2 to C18 : 3. These results strongly supported that CaFAD2 encodes the Delta12 FAD and that CaFAD3 encodes the omega3 FAD. However, phenotypic analysis demonstrated that the presence of these PUFAs did not affect the virulence to mice, or morphogenesis in the culture media used to induce morphological change of C. albicans.

Topics: alpha-Linolenic Acid; Amino Acid Sequence; Animals; Candida albicans; Candidiasis; Disease Models, Animal; Fatty Acid Desaturases; Fatty Acids; Fatty Acids, Monounsaturated; Gas Chromatography-Mass Spectrometry; Gene Deletion; Linoleic Acid; Male; Mice; Mice, Inbred ICR; Molecular Sequence Data; Mutagenesis, Insertional; Recombinant Proteins; Saccharomyces cerevisiae; Sequence Homology, Amino Acid; Virulence

The authors investigated whether fatty acid emulsion affects the blood-brain barrier (BBB), whether disrupted BBB is reversible, and whether the fatty acid emulsion technique may be a model for BBB research.. The fat emulsion was made with 0.05 mL of oleic acid or linoleic acid and 20 mL of normal saline. The internal carotid artery in 14 cats was infused with oleic acid emulsion (group 1) and with linoleic acid emulsion in 12 cats (group 2). Gd-enhanced T1-weighted (Gd-T1WI), diffusion-weighted (DWI), and additional apparent diffusion coefficient (ADC) map magnetic resonance imaging (MRI) was obtained at 1 hour, 1 and 4 days, and 1 week after infusion. MRI findings were evaluated qualitatively. Quantitatively, the signal intensity ratio (SIR) of the lesion to the contralateral hemisphere was measured on Gd-T1WIs. The SIRs were statistically analyzed using the student t test. The brain tissue was removed immediately for light and electron microscopy examination if the lesion showed no contrast enhancement and was isointense on DWIs and the ADC maps.. The lesions appeared at 1 hour in both groups as contrast enhancement on Gd-T1WIs, as isointensity or mild hyperintensity on DWIs, and as isointensity on the ADC maps. On day 1, these MRI findings were decreased in group 1 and were not seen in group 2. At 1 hour, the SIRs of group 1 were significantly higher than those of group 2 (P = 0.016). On day 1, the SIRs of both groups approximated 1.0. Light microscopy findings revealed minor necrosis and demyelination in one cat from group 1 and in 3 cats from group 2. Electron microscopy examinations showed minimal findings in the cortical lesions in groups 1 and 2.. Infusion of unsaturated fatty acid emulsion into the carotid artery of cats revealed vasogenic edema of the brain and reversible changes as depicted on MRI. This unsaturated fat emulsion technique may be used as a model for research on BBB disruption.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Carotid Artery, Internal; Cats; Demyelinating Diseases; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Emulsions; Gadolinium DTPA; Image Enhancement; Injections, Intra-Arterial; Linoleic Acid; Necrosis; Oleic Acid; Time Factors

In the Long-Evans Cinnamon rat, copper accumulates in the liver because of a mutation in the copper-transporting ATPase gene, and peroxidative stresses are supposed to be augmented. We examined the effects of dietary fatty acids on hepatitis, hepatic gene expression, and survival. Rats were fed a conventional, low-fat diet (CE2), a CE2 diet supplemented with 10 wt% of lard (Lar), high-linoleic soybean oil (Soy), or a mixture of docosahexaenoic acid (DHA)-rich fish oil and soybean oil (DHA/Soy). Among female rats, the mean survival times of the DHA/Soy and the Soy groups were longer by 17 approximately 20% than in the Lar and the CE2 groups. Among male rats, the survival times were much longer than in the females, but no significant difference in survival was observed among the dietary groups. Serum ceruloplasmin levels in female and male rats of all of the dietary groups were similar. Serum transaminase levels of the DHA/Soy group tended to be lower than in the CE2 group. Histological examinations revealed a marked degeneration in hepatic tissue integrity in the Lar and CE2 groups but not in the DHA/Soy group. Hepatic levels of metal-related genes, transferrin and ceruloplasmin, as well as those related to bile acid synthesis were up-regulated, and an inflammation-related gene (cyclooxygenase [COX]-2) was down-regulated in the DHA/Soy group. Some proliferation-related genes were also affected by the dietary fatty acids. These results indicate that polyunsaturated fatty acids suppress the development of acute hepatitis and prolong survival in females, regardless of whether they are of the n-6 or n-3 type, which are associated with altered gene expressions.

Topics: Acute Disease; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dietary Fats, Unsaturated; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Unsaturated; Female; Fish Oils; Gene Expression; Hepatitis; Hepatolenticular Degeneration; Isoenzymes; Linoleic Acid; Liver; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred LEC; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Soybean Oil; Survival Rate

We investigated the cellular and molecular immunoregulatory actions of conjugated linoleic acid (CLA) of relevance to viral disease pathogenesis and antiviral responses. To test the hypothesis that CLA ameliorates viral disease, we developed a viral challenge model by infecting pigs with type-2 porcine circovirus (PCV2). After 42 d of dietary supplementation with either soybean oil (n = 16) or CLA (n = 16), half of the pigs in each group were challenged with PCV2. We examined the effect of CLA on the development of lesions (i.e., lymphoid depletion and pneumonia) and observed the kinetics of the immune responses against PCV2. The viral infection depleted immature B cells (IgM+SWC3+) and favored proapoptotic mRNA expression profiles [i.e., suppressed B-cell leukemia/lymphoma-xl (Bcl-xl) and stimulated Bcl-2 homologous antagonist/killer (Bak)] in the external inguinal lymph nodes. B-cell depletion was more accentuated in pigs fed the control diet, whereas interleukin (IL)-2 mRNA expression was downregulated. Histopathological examination of the lungs revealed that the interstitial pneumonia tended to be more severe in infected pigs fed the control diet, which were also affected by growth retardation. CD8+ T cells were the primary cellular targets of CLA action in peripheral blood (CD8+CD29low and CD8+CD45RC+) and thymus (CD8+ and CD4+CD8+). CLA interacted with PCV2 to increase the proliferation of CD8+ T cells and to suppress PCV2-specific interferon (IFN)-gamma production in CD4+ T cells. At the molecular level, these cellular immunoregulatory properties were associated with differential patterns of peroxisome proliferator-activated receptor (alpha and gamma) mRNA expression between diets in virally infected pigs.

Topics: Animals; Antibody Formation; Apoptosis; B-Lymphocytes; bcl-2 Homologous Antagonist-Killer Protein; bcl-X Protein; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Circoviridae Infections; Circovirus; Dietary Fats, Unsaturated; Disease Models, Animal; Gene Expression; Immune Tolerance; Immunophenotyping; Interferon-gamma; Interleukin-12; Interleukin-18; Interleukin-2; Linoleic Acid; Lung; Lymph Nodes; Lymphocyte Activation; Lymphopenia; Membrane Proteins; Pneumonia, Viral; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Swine; Transcription Factors

The present study explored the short-term effects of dietary conjugated-linoleic acid (CLA) on liver lipid metabolism in starved/refed Otsuka Long Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (12 weeks old) were starved for 24 hours, then refed for 48 hours with either a CLA diet [7.5% CLA and 7.5% Safflower oil (SAF)] or a SAF control diet (15% SAF). The results demonstrated a 30% reduction of hepatic triglyceride (TG) concentration in the CLA group when compared to the control group. Liver cholesterol concentration was also 26% lower in the CLA fed rats. The activity of mitochondrial carnitine palmitoyltransferase, the rate-limiting enzyme of fatty acid oxidation, was moderately elevated by 1.2-fold in the livers of the CLA group when compared to the control. In contrast, phosphatidate phosphohydrolase, the rate-limiting enzyme for TG synthesis, was found to be 20% lower in the livers of the CLA-fed rats. Therefore, dietary CLA evidently lowers liver lipid concentrations through a reduced TG synthesis and enhanced fatty acid oxidation in starved/refed OLETF rats.

Topics: Animals; Carnitine O-Palmitoyltransferase; Diabetes Mellitus, Type 2; Dietary Fats; Disease Models, Animal; Food; Glucosephosphate Dehydrogenase; Linoleic Acid; Liver; Malate Dehydrogenase; Male; Phosphatidate Phosphatase; Rats; Rats, Inbred OLETF; Starvation; Triglycerides

Topics: Adenoma; Animals; Anticarcinogenic Agents; Colonic Neoplasms; Disease Models, Animal; Drinking; Fatty Acids; Genes, APC; Linoleic Acid; Male; Mice; Mice, Mutant Strains; Random Allocation

Tumor necrosis factor-alpha (TNF) is an immunoregulatory cytokine that plays a major role in tumor-induced anorexia and weight loss. Conjugated linoleic acids (CLA) are naturally occurring isomers of linoleic acid that, when added to the diet, improve food intake and body weight in mice injected with TNF. The purpose of the present study was to examine the effects of a diet supplemented with 0.5% CLA on the nutritional status of rats implanted with the Morris 7777 hepatoma. Body weight, food intake, serum levels of insulin-like growth factor, and splenocyte synthesis of TNF were not different in tumor-bearing animals fed CLA versus the control diet. However, insulin levels were increased in both tumor-bearing and control animals given CLA. The 0.5% CLA did not improve the nutritional status nor alter TNF synthesis in hypophagic tumor-bearing rats. The biological significance of increased insulin levels in animals given CLA remains to be determined.

Topics: Analysis of Variance; Animals; Anorexia; Body Weight; Dietary Supplements; Disease Models, Animal; Drug Evaluation, Preclinical; Energy Intake; Insulin; Insulin-Like Growth Factor I; Linoleic Acid; Liver Neoplasms, Experimental; Male; Mice; Nutritional Status; Rats; Rats, Inbred BUF; Tumor Necrosis Factor-alpha; Wasting Syndrome

We investigated in bile duct-ligated (BDL) and sham-operated control rats whether the frequent presence of essential fatty acid deficiency in cholestatic liver disease could be related to linoleic acid malabsorption, altered linoleic acid metabolism, or both. In plasma of BDL rats, the triene-to-tetraene ratio, a biochemical marker for essential fatty acid deficiency, was increased compared with controls (0.024 +/- 0.004 vs. 0.013 +/- 0.001; P < 0.05). Net and percentage of dietary linoleic acid absorbed were decreased in BDL rats compared with control rats (1.50 +/- 0.16 mmol/day and 81.3 +/- 3.3% vs. 2.08 +/- 0.07 mmol/day and 99.2 +/- 0.1%, respectively; each P < 0.001). At 24 h after [(13)C]linoleic acid administration, BDL rats had a similar ratio of plasma [(13)C]arachidonic acid to plasma [(13)C]linoleic acid concentration compared with control rats. Delta(6)-Desaturase activity was not significantly different in hepatic microsomes from control or BDL rats. At 3 h after [(13)C]linoleic acid administration, plasma appearance of [(13)C]linoleic acid and cumulative expiration of (13)CO(2) were decreased in BDL rats, compared with controls (by 54% and 80%, respectively). The present data indicate that the impaired linoleic acid status in cholestatic liver disease is mainly due to decreased net absorption and not to quantitative alterations in postabsorptive metabolism.

Topics: Animals; Bile Ducts; Biomarkers; Body Weight; Cholestasis; Disease Models, Animal; Energy Intake; Intestinal Absorption; Ligation; Linoleic Acid; Liver; Male; Rats; Rats, Wistar

Long-term ethanol consumption in laboratory animals is associated with histological alterations of liver cells and modifications of fatty acid metabolism.. The present study was aimed at investigating the effect of 1- and 2-month chronic treatment of rats with ethanol on the metabolism of two unsaturated (oleic and linoleic) fatty acids in liver and kidney microsomes, in relation to the CYP2E1 enzyme content in both tissues.. Rats were fed ethanol (14 g/Kg/d) or dextrose through a permanently implanted gastric cannula, as described in the intragastric feeding rat model for alcoholic liver disease (ALD). CYP2E1 level was immuno-quantified in both liver and kidney microsomes by Western blot, whereas fatty acid omega- and (omega-1)-hydroxylations were measured using HPLC and radiometric analytical methods.. One- and two-month ethanol treatment led to a 3- to 4-fold rise of the CYP2E1 protein in both liver and kidney microsomes. Oleic and linoleic acid (omega-1)-hydroxylations were increased (approximately 3-fold) in liver microsomes after one-month of ethanol administration, but surprisingly such a rise was not observed after a two-month treatment; on the other hand, no effect was observed on the omega-hydroxylations of these fatty acids. Furthermore, as previously described for lauric acid, ethanol intake did not significantly act on the kidney microsome capability to hydroxylate unsaturated fatty acids.. CYP2E1 is strongly inducible by ethanol and therefore accounts for the tolerance for this hepatotoxicant. Our results support the development of an adaptation process in the liver hydroxylating enzyme system, which occurs between one and two months of ethanol feeding. Although it is usually not appropriate to extrapolate animal findings to humans, rat and human CYP2E1s were observed to have comparable specificities and similar mechanisms of regulation. Thus, the present study allowed the acquirement of detailed information of CYP2E1 activity in patients with severe manifestations of ALD.

Topics: Adaptation, Physiological; Animals; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2E1; Disease Models, Animal; Drug Tolerance; Ethanol; Glucose; Hydroxylation; Kidney; Linoleic Acid; Liver Diseases, Alcoholic; Male; Microsomes; Microsomes, Liver; Oleic Acid; Rats; Rats, Wistar

Insulin resistance can be induced by diets high in simple carbohydrates or fatty acids. To determine whether these nutrients also affect arterial pressure in genetic models of salt sensitive and salt resistant hypertension, Dahl salt sensitive (S) and salt resistant (R) rats were each fed the following isocaloric diets containing 3% NaCl for 4 weeks (10 rats/group): 1) control; 2) high sucrose (60%); 3) high linoleic acid (LA, provided as 10% safflower oil); and 4) high sucrose plus high LA. Tail systolic blood pressures (SBP) were measured weekly, and at 4 weeks, direct mean arterial pressures (MBP) were measured in conscious animals. Insulin sensitivity was assessed by in vitro uptake of tritiated glucose by adipocytes in response to graded doses of insulin. Weight gain did not differ among groups. High sucrose alone and high LA alone did not affect blood pressure in either strain. However, SBP and MBP were increased (P < .05) by the high sucrose plus high LA diet in Dahl-S but not in Dahl-R rats. Sucrose alone and LA alone decreased (P < .05) insulin sensitivity in Dahl-S and Dahl-R rats. In both strains, sucrose plus LA decreased insulin sensitivity to a greater extent (P < .05) than sucrose alone or LA alone. Thus, the sucrose plus LA diet decreased insulin sensitivity in both Dahl-S and Dahl-R rats, whereas blood pressure was increased only in Dahl-S rats. The phenotype of elevated arterial pressure is influenced both by a genetic-nutrient interaction and by an interaction among specific nutrients resulting in insulin resistance.

Topics: Adipocytes; Animals; Blood Glucose; Blood Pressure; Dietary Fats, Unsaturated; Dietary Sucrose; Disease Models, Animal; Follow-Up Studies; Hypertension; Insulin; Insulin Resistance; Linoleic Acid; Male; Rats; Rats, Inbred Dahl; Sodium Chloride

Topics: Animals; Arteriosclerosis; Diet; Disease Models, Animal; Humans; Linoleic Acid; Lipids

Recent studies have shown that long-chain polyunsaturated fatty acids can prevent cardiac arrhythmias, attributed to the reduction in excitability of cardiomyocytes, owing mainly to a shift in hyperpolarizing direction of the inactivation curves of both Na+ and Ca2+ currents and to a slowed recovery from inactivation. Qualitatively similar effects of polyunsaturated fatty acids on inactivation parameters have been observed in freshly isolated hippocampal neurons. Since the same effects are presumed to underlie the action of some established anticonvulsant drugs, polyunsaturated fatty acids might have an anticonvulsant action as well. We have investigated this for eicosapentaenoic acid, docosahexaenoic acid, linoleic acid and oleic acid, employing cortical stimulation in rats, a seizure model allowing the determination of the full anticonvulsant effect-time profile in freely moving, individual animals. I.v. infusion of 40 micromol of eicosapentaenoic acid or docosahexaenoic acid over a period of 30 min, modestly increased the threshold for localized seizure activity after 6 h by 73 +/- 13 microA (mean +/- S.E.M.; n = 7) and 77 +/- 17 microA (n = 7), respectively, and the threshold for generalized seizure activity by 125 +/- 20 and 130 +/- 19 microA, respectively (P < 0.001). The thresholds remained elevated for 6 h after infusion, but returned to baseline the next day. Free plasma concentrations in rats treated with eicosapentaenoic acid or docosahexaenoic acid, averaged 5.7 +/- 1.6 microM (n = 4) for eicosapentaenoic acid and 12.9 +/- 1.8 microM (n = 5) for docosahexaenoic acid at the end of infusion, but declined to undetectable levels within 3 h. Linoleic acid and oleic acid were less effective. Possible mechanisms for the modest anticonvulsant effect but of long duration with the polyunsaturated fatty acids are discussed.

Topics: Animals; Disease Models, Animal; Docosahexaenoic Acids; Electric Stimulation; Fatty Acids, Unsaturated; Linoleic Acid; Male; Oleic Acid; Outcome Assessment, Health Care; Rats; Rats, Wistar; Seizures; Valproic Acid

An experimental model of chronic pancreatitis was induced by a retrograde injection of a viscous solution consisting of zein-oleic acid-linoleic acid (0.05 ml/100 g body weight) into the rat pancreatic duct. Histologic and biochemical changes were investigated over a period of 6 months after induction of this model. The treated rats gained weight, but pancreatic weight decreased with time. Histologically, the widening of acinar lumen and cellular vacuolization occurred within 24 h at the parenchyma neighboring the small ducts filled with the injected solution. Degenerative parenchyma, interstitial edema, and inflammatory cell infiltration were pronounced 1 week later. Thereafter, duct-like tubular complex formation progressed, and the exocrine tissue exhibited marked atrophy of the gland with irregular fibrosis and fat replacement over a period of 6 months. Pancreatic contents of protein, amylase, DNA, and RNA markedly decreased, as did pancreatic weight, whereas hydroxyproline content increased. Oral administration of camostat did not affect pancreatic weight and contents of enzyme in this model. Urinary para-aminobenzoic acid (PABA) excretion in the BT-PABA test decreased to 54% at 6 weeks and 22% at 6 months. Although three quarters of pancreatic immunoreactive insulin (IRI) content was lost after 6 months, overt diabetes did not occur. The results suggest that an obstructive mechanism in the small ducts plays an important role in the genesis and development of chronic pancreatitis.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Chronic Disease; Disease Models, Animal; Esters; Gabexate; Guanidines; Linoleic Acid; Male; Oleic Acid; Organ Size; Pancreas; Pancreatic Ducts; Pancreatitis; Protease Inhibitors; Rats; Rats, Wistar; Solutions; Survival Rate; Zein

Rats were fed diets containing different ratios of linoleate (18:2 n-6) to alpha-linolenate (18:3 n-3), and the severity of gastric injury induced by ethanol, ischemia/reperfusion and water-immersion stress was compared. On decreasing the 18:2 n-6/18:3 n-3 ratios in the diets, the proportion of arachidonic acid (20:4 n-6) decreased and that of eicosapentaenoic acid (20:5 n-3) increased in the phospholipids of the gastric mucosa, which was associated with decreased mucosal prostaglandin E2 content. Mucosal injury in all the three experimental models was exacerbated significantly in the diet group fed 18:2 n-6/18:3 n-3 ratio of 0.25 (perilla oil) as compared with the groups fed dietary oils with 18:2 n-6/18:3 n-3 ratios of 2.7 (mixture of perilla and safflower oils) and 127 (safflower oil). This adverse effect induced by perilla oil diet was not observed when rats were pretreated with a mild irritant (20% ethanol) prior to challenge with a strong irritant (absolute ethanol). Furthermore, an 18:2 n-6/18:3 n-3 ratio of as low as 1 was found to be in a safe range in the water-immersion stress ulcer model. Thus, oils with very low n-6/n-3 ratios, for example perilla oil, could be used without the risk of the observed adverse effects on experimental gastric injury in people of industrialized countries ingesting foods with n-6/n-3 ratios of above 4. A decrease in the n-6/n-3 ratios to 2 or below is still recommended for the prevention of chronic diseases in the elderly related to atherosclerosis and inflammation.

Topics: alpha-Linolenic Acid; Animals; Diet; Dietary Fats, Unsaturated; Dinoprostone; Disease Models, Animal; Ethanol; Fatty Acids; Gastric Acid; Gastric Mucosa; Linoleic Acid; Male; Pepsin A; Phospholipids; Plant Oils; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stomach Ulcer

To study the influence of dietary fatty acids on arterial thrombosis tendency 65 groups of male rats were fed diets containing 50% of their digestible energy as fat from 32 different oils and fats. After 8 weeks their arterial thrombosis tendency was assessed by measuring the obstruction time (OT) of a loop-shaped polythene cannula inserted into the abdominal aorta. Using multiple regression analysis log10 OT was modelled as a function of the relative amounts of the various dietary fatty acids and their combinations. The best fit (R2 = 0.79) was obtained for the sums of all monoenoic and (n-6) and (n-3) polyenoic fatty acids, which appeared antithrombotic. The fit for the sum of all saturated fatty acids, which had a prothrombotic effect, was almost as good (R2 = 0.76). The ratio between dietary polyunsaturated and saturated fatty acids (P:S ratio) appeared a strong predictor of arterial thrombosis tendency (R2 = 0.77). Marine oils did not have a more powerful antithrombotic effect than could be expected on the basis of their P:S ratios. Using stepwise regression analysis myristic acid, 14:0, was shown to be the strongest prothrombotic fatty acid whereas linoleic acid, 18:2(n-6), was the strongest antithrombotic fatty acid. Since the number of marine oils was very limited the effects of the 'fish fatty acids' eicosapentaenoic acid, 20:5(n-3) and docosahexaenoic acid, 22:6(n-3), on arterial thrombus formation could not be tested reliably. The same appeared true for gamma-linolenic acid, 18:3(n-6), and stearidonic acid, 18:4(n-3), present in a few vegetable oils only.

Topics: Animals; Arterial Occlusive Diseases; Dietary Fats; Dietary Fats, Unsaturated; Disease Models, Animal; Energy Intake; Fatty Acids; Fatty Acids, Unsaturated; Fish Oils; Linoleic Acid; Linoleic Acids; Male; Myristic Acid; Myristic Acids; Rats; Rats, Wistar; Regression Analysis; Thrombosis

This study examined the possible effects of a novel mixture of fatty acids, SR-3 (a specific ratio of alpha-linolenic acids), on brain biochemistry and on learning deficits induced by injection of an agent that induces experimental allergic encephalomyelitis. Treatment with SR-3 caused a decrease in myelin and changes in the fatty acid profile of brain synaptosomes, and a learning deficit. Eighteen days of treatment with SR-3 reversed the biochemical and learning deficit significantly, but did not restore them to normal levels. We propose that, most probably, the main action of SR-3 is the modulation of the cholesterol level, which in turn causes the modulation of the fatty acid profile and enhances learning by allowing improved neuronal communication.

Topics: alpha-Linolenic Acid; Analysis of Variance; Animals; Avoidance Learning; Body Temperature; Body Weight; Brain; Brain Chemistry; Cholesterol; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fatty Acids, Essential; Learning; Linoleic Acid; Male; Maze Learning; Motor Activity; Myelin Sheath; Rats; Rats, Inbred Lew; Synaptosomes

Controlled feeding of linoleic acid (LA) or arachidonic acid (AA) to essential fatty acid-deficient (EFAD) rats was used to define the relationship between dietary AA and the inflammatory response evoked during adjuvant-induced arthritis. Based on energy percentage, EFAD rats were fed AA at the human daily equivalent (1x; 5.5 mg/day) or 10 times that amount (10x; 55 mg/day) or, alternatively 0.5x of LA (273 mg/day). Feeding of 0.5x LA restored the plasma level of AA to that in chow-fed controls. In contrast, feeding of 1x AA only partially restored the plasma level of AA; 10x AA was required to fully replete AA. In parallel to the degree of repletion of AA in plasma, there were accompanying decreases in the levels of palmitoleic acid, oleic acid, and Mead acid. Compared to rats fed the standard laboratory chow diet (Control), edema in the primary hind footpads was decreased by 87% in EFAD, 71% in EFAD + 1x AA, 45% in EFAD + 10x AA, and 30% in EFAD + 0.5x LA. The decrease in edema in the footpads of EFAD rats was nearly identical to the decrease in edema in the footpads of Control rats dosed with indomethacin. Hind footpad edema correlated with the final AA plasma level and eicosanoid levels extracted from hind footpad tissue, but not with neutrophil infiltration. The data showed that 0.5x LA and 10x AA, but not 1x AA, could quickly replete AA, accompanied by the synthesis of AA-derived eicosanoids and restoration of edema. These results suggest that in humans consumption of the average daily amount of AA without concurrent ingestion of LA would not alleviate an EFAD state.

Topics: Animals; Arachidonic Acid; Arthritis, Experimental; Body Weight; Dietary Fats; Disease Models, Animal; Eicosanoids; Energy Intake; Fatty Acids; Fatty Acids, Essential; Humans; Indomethacin; Linoleic Acid; Male; Neutrophils; Peroxidase; Rats; Rats, Inbred Lew; Time Factors

The purpose of this study was to evaluate the interaction of a linoleic acid enriched diet with NaCl on the development of hypertension in Dahl salt sensitive (Dahl-S) rats and in two-kidney, one-clip Sprague Dawley rats.. In both experimental models, separate groups of animals were fed either linoleic acid enriched (provided as safflower oil) or control (containing coconut oil) diets for 5 weeks. Diets were further subdivided on the basis of either a low NaCl (0.3%) or a high NaCl (3.0%) content. Tail systolic blood pressure, direct mean intra-arterial pressure, and cardiac output were measured in chronically instrumented, conscious rats.. In Dahl-S, on both NaCl intakes, and in two-kidney, one-clip rats on a high NaCl diet, safflower oil had no effect on arterial pressure. In contrast, in two-kidney, one-clip rats fed the low NaCl diet, both indirect tail systolic blood pressures and direct mean arterial pressure were lower (p<0.01) in animals on the linoleic acid enriched diet; total peripheral resistance was also decreased (p<0.01).. Safflower oil has a hypotensive effect only in the two-kidney, one-clip rat on a low NaCl, but not on a high NaCl intake, and not in Dahl-S rats. Additional studies are required to identify the mechanism(s) for the hypotensive effect of safflower oil and to define the relationship of this animal study to human hypertension.

Topics: Animals; Dietary Fats; Disease Models, Animal; Hypertension; Linoleic Acid; Linoleic Acids; Male; Rats; Rats, Sprague-Dawley; Sodium Chloride; Species Specificity

Outer segments of the photoreceptor rods that are phagocytized by the retinal pigment epithelial (RPE) cells contain a high proportion of polyunsaturated fatty acids (PUFA). PUFA are susceptible to lipid peroxidation. We hypothesized that the resulting peroxides could injure RPE cells leading to retinal degeneration. Accordingly, we compared the effects of linoleic acid (LA) and its hydroperoxide (LHP) on the growth and morphology of RPE cells using laser scanning microscopy and transmission microscopy.. We counted the number of RPE cells after incubation for 24 and 48 hrs with concentrations of LA or LHP of 0.035, 0.175, and 0.35 mM. To observe the actin filaments, cultured RPE cells were stained with rhodamine phalloidin. The cells were prefixed with 2% glutaraldehyde and postfixed in 1% osmium tetroxide. Specimens were embedded in Epon 812 after dehydration, and the ultrathin sections were doubly stained with 2% uranyl acetate and 2% lead acetate for examination by transmission electron microscopy.. Exposure to LA or LHP produced dose-dependent damage to RPE cells with a significantly greater effects of LHP than LA. After incubation for 24 hrs with 0.35 mM LA, the number of vacuoles in RPE cells exceeded that observed in control RPE cells by 365 nm laser microscopy. Exposure to 0.35 mM LHP for 24 hrs produced a pycnotic nucleus, with diffuse and granular autofluorescences observed in and around it. Exposure of RPE cells to 0.35 mM LA for 24 hrs showed that the LA incorporated into the lysosomes was digested and released extracellularly from lysosomes via exocytotic vesicles. However, such exposure to LHP damaged the RPE cells, including the membranes in the pinocytotic vesicles. The packed membranes resembled myelin.. While the LA incorporated into the lysosomes was released extracellularly, LHP persisted in the RPE cells, being observed as autofluorescent lipofuscin-like materials. LHP was cytotoxic, and caused damage to the membranes of pinocytotic vesicles and lysosomes.

Topics: Animals; Cattle; Cell Division; Disease Models, Animal; In Vitro Techniques; Linoleic Acid; Linoleic Acids; Lipid Peroxidation; Lipid Peroxides; Lysosomes; Microscopy, Electron; Microscopy, Electron, Scanning; Pigment Epithelium of Eye; Pinocytosis; Retinal Degeneration

The potential involvement of individual fatty acids from diet or from adipose tissue in the outcome of cancer emphasizes the need for more insight into the relationship between fatty acids and tumor growth. The main objective of the present study was to examine whether rapid tumor growth would induce changes in the fatty acid composition of adipose tissue, indicating selective use and thus deposition of dietary fatty acids and/or selective removal of stored fatty acids from adipose tissue. We used a rodent model of transplanted solid tumor (Yoshida sarcoma) and measured the fatty acid composition from different adipose sites in the absence and in the presence of tumor but at the same intake of dietary fatty acids. We found that Yoshida sarcoma could grow rapidly without significantly altering the fatty acid composition of adipose tissue, irrespective of its location. These results do not favor the hypothesis of a selective removal of fatty acids from adipose tissue by growing tumors. They moreover indicate that tumors do not modify the storage of individual dietary fatty acids.

Topics: Adipose Tissue; Animals; Body Mass Index; Diet; Disease Models, Animal; Fatty Acids; Linoleic Acid; Linoleic Acids; Male; Neoplasm Transplantation; Rats; Rats, Wistar; Sarcoma, Yoshida

We tested the hypothesis that an increased content of n-6 polyunsaturated fatty acids (principally linoleic acid) in an atherogenic diet of nonhuman primates would decrease atherosclerosis by modifying the composition and decreasing the concentration of plasma low-density lipoprotein (LDL). A species readily susceptible to diet-induced atherosclerosis (cynomolgus monkey) was compared with a less-susceptible species (African green monkey) with dietary cholesterol concentration and saturated or polyunsaturated fat (40% of energy) as variables. In both species, cholesterol concentrations in whole plasma, LDL, and high-density lipoprotein (HDL) were 20-30% lower when polyunsaturated fat was fed, whereas dietary cholesterol increased LDL cholesterol three- to fourfold. LDL was enriched in cholesteryl oleate when saturated fat and cholesterol were fed. Dietary linoleic acid prevented cholesteryl oleate enrichment and promoted cholesteryl linoleate accumulation in LDL. At the same plasma cholesterol concentration, cynomolgus monkeys had higher LDL cholesterol and lower HDL-cholesterol concentrations than did African green monkeys. LDL particle size was significantly (P < 0.001) larger in the group of cynomolgus monkeys fed polyunsaturated fat but tended to be smaller in African green monkeys fed polyunsaturated fat. Dietary polyunsaturated fat protected against coronary artery atherosclerosis in both species. Thus, LDL particle size, per se, was not atherogenic; instead, coronary artery atherosclerosis and cholesteryl oleate enrichment of LDL were more highly correlated. This outcome suggests that information about LDL composition may be more important for understanding the pathogenesis of atherosclerosis than previously suspected.

Topics: Animals; Arteriosclerosis; Chlorocebus aethiops; Cholesterol, HDL; Dietary Fats, Unsaturated; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Linoleic Acid; Linoleic Acids; Lipoproteins, HDL; Lipoproteins, LDL; Macaca fascicularis; Male

Fish oil, rich in n-3 polyunsaturated fatty acids, can alter leukotriene production and hence neutrophil function, factors which may be important in the inflammation of Crohn's disease (CD). Therefore we studied the effect of dietary PUFA on neutrophil mediated ileal inflammation and neutrophil function in the rat.. Animals were ad libitum-fed pellet diets containing 9.5% fish oil (menhaden oil, rich in n-3 PUFA) with 0.5% safflower oil, 10% safflower oil (rich in n-6 PUFA) or standard chow (6% fat) for 50 days prior to the study. Weight and circulating leukocyte and total neutrophil counts were identical in all three groups. Neutrophil mediated ileal inflammation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) perfusion was evaluated by measuring macromolecular uptake of radiolabelled dextran (MW 70,000) and changes in mucosal neutrophil infiltration.. The fish oil diet group showed no difference in fMLP-induced permeability changes relative to the Chow Control group. However, the Safflower Oil supplemented diet group had a reduced permeability response (p < 0.01). Mirroring the permeability changes, there was diminished mucosal neutrophil infiltration in the Safflower Oil group following ileal perfusion with fMLP (< .005). Chemotaxis and chemiluminescence, two important neutrophil functions, were also significantly suppressed in the Safflower Oil animals (p < 0.05).. The failure of a n-3 PUFA enriched diet to diminish the ileal inflammatory response to a bacterial peptide and suppress neutrophil function in the rat suggests such therapy would not be expected to be highly successful in CD. However, it requires confirmation in man, especially under the more complicated inflammatory conditions found in CD. On the other hand, the decreased neutrophil mediated responses with a high linoleic acid (n-6 PUFA) diet warrant further investigation.

Topics: Animals; Chemotaxis, Leukocyte; Crohn Disease; Dextrans; Disease Models, Animal; Fatty Acids, Omega-3; Food, Fortified; Ileum; Leukotrienes; Linoleic Acid; Linoleic Acids; Luminescent Measurements; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Permeability; Rats; Rats, Sprague-Dawley

Obese Zucker rats (fa/fa) have low levels of arachidonic acid (AA) in liver phospholipids (PL). We have previously shown that a 70% gamma-linolenate concentrate (GLA; an AA intermediate) fed at a fixed dose (0.07 g/day) normalized hepatic PL AA and reduced weight gain selectively in the obese animals. In a follow-up study, 16 obese (fa/fa) and 16 lean (Fa/Fa) 4-week-old male rats were randomized into 4 groups of 8 each and gavaged daily with soybean oil (SOY) containing 55% 18:2omega6 (an AA precursor) or GLA, using a progressive dose (< or = 5% of total calories) based on body weight. A defined diet with 11% of energy as SOY was fed ad libitum for 60 days. GLA obese had lower body weight (p<0.0001) and 60-day cumulative food intake (p<0.05) compared to SOY obese, but neither parameter differed between the lean groups. For the last twenty days cumulative food intake was identical for GLA obese and SOY lean, whereas SOY obese consumed 18% more (p<0.05). Thus the progressive dose of GLA selectively suppressed hyperphagia in obese Zucker rats. Erythrocytes collected at 15-day intervals showed parallel increases in AA in both genotypes over time, suggesting normal AA availability during rapid growth. Thus, the reduced PL AA in the livers from the obese rats probably reflects impaired distribution in selected tissues rather than reduced hepatic production. Due to the potential health risks of enriching tissue lipids with AA, great caution is advised in considering GLA as therapy for human obesity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Composition; Body Weight; Dietary Supplements; Disease Models, Animal; Eating; Energy Metabolism; Erythrocytes; Fatty Acids; gamma-Linolenic Acid; Genotype; Glycine max; Growth; Hyperphagia; Linoleic Acid; Lipid Metabolism; Lipids; Liver; Male; Obesity; Phospholipids; Rats; Rats, Zucker; Time Factors; Weight Gain

Quick model of experimental atherosclerosis--3 weeks of cholesterol feeding and 3 weeks of standard diet for aorta atheromatosis development--was used in rabbits. Then one group of animals was fed 1 month by plant oil of specific composition, with added omega-3 (linolenic) fatty acid, and the other group received the same dose of fish oil. The most intensive decrease of plasma cholesterol and erythrocyte cholesterol/phospholipid ratio was in rabbits, that received the oil with linolenic acid. Triglyceride level decreased gradually in all animal groups in the same degree, and HOL cholesterol did not change. After the end of experiment the aorta damage degree in group, that received plant oil with linolenic acid, was only 10.8%, as compared with 36.2% in control group (without treatment) and 39.3% in rabbits, that received fish oil. The absence of fish oil effect supports the earlier data about rabbits specific sensitivity to this product resulting in possible hepatotoxic effect. The data indicates on the usefulness of rabbit model in fish oil effects investigations, and also on the positive, antiatherogenic effect of plant oil with added linolenic acid.

Topics: Animals; Arteriosclerosis; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fatty Acids, Omega-3; Fish Oils; Linoleic Acid; Linoleic Acids; Male; Plant Oils; Rabbits; Time Factors

We tried to develop an experimental model using mice for the primary screening of antiatherosclerotic agents. Male ICR strain mice were given a high-cholesterol diet supplemented with 10% linoleic acid for 14 weeks. Throughout the experimental period, weight gain of these mice was significantly inhibited as compared to that of control mice given a basal diet, but displayed a steady increase comparable to that of the high-cholesterol diet without linoleic acid. The cholesterol and linoleic acid-fed mice showed increased serum cholesterol and phospholipid levels, and decreased serum triglyceride and high-density lipoprotein-(HDL) cholesterol levels and lecithin/cholesterol acyltransferase (LCAT) activity, as well as a markedly increased lipid peroxide level which was a characteristic appearance in the serum of this mouse model. At the end of the experiment, uniform and significant increases in cholesterol, notably cholesteryl ester, were observed in the aorta. Also found were marked decreases in the aorta contents of desmosine and isodesmosine, which are cross-linking amino acids present only in the elastin. Histological observations showed accumulations of fatty droplets in the intima. These changes were much less in mice receiving a high-cholesterol diet without linoleic acid. In this mouse model, probucol prevented elevation of serum cholesterol, phospholipid, and cholesterol accumulation in the aorta. Increases in lipid peroxide level and decreases in LCAT activity were also prevented. These findings indicate that this mouse model is useful for primary screening of antiatherosclerotic agents with antioxidative activity.

Topics: Animals; Anticholesteremic Agents; Aorta; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Desmosine; Disease Models, Animal; Drug Evaluation, Preclinical; Hypercholesterolemia; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Lipids; Male; Mice; Mice, Inbred ICR; Phosphatidylcholine-Sterol O-Acyltransferase; Probucol

To test for a regulatory defect in adipose triacylglycerol (essential) fatty acid mobilization in lymphoma-bearing mice, free [1-14C]linoleic acid/mouse serum albumin was injected iv into lymphoma-bearing and control mice, adapted to a reversed light cycle, and studied in three dietary states in the dark period. Mean daily food intake decreased in mice with small and large tumor burdens. Plasma free fatty acid (FFA) oxidation rates, which approximate FFA mobilization rates, were estimated by multicompartmental analysis (CONSAM). Oxidation of linoleate to CO2 was reduced significantly (85%) in ad libitum fed as compared to briefly fasted control mice but not in fed vs. fasted mice with large or small tumor burdens. However, plasma FFA oxidation rates to CO2 did not differ in briefly fasted tumor-bearing and pair-fed control mice. When re-fed a 250-mg test meal, briefly fasted mice with small tumors suppressed plasma free linoleic acid oxidation, as did controls. During simulated night, mildly anorexic, tumor-bearing mice with small tumor burdens mobilized essential fatty acids much faster than controls. This could explain body fat loss. The abnormally rapid rates of FFA (free linoleic acid) mobilization at night probably result from anorexia rather than from inability of food to suppress fat mobilization.

Topics: Animals; Anorexia; Appetite Depressants; Appetite Regulation; Body Burden; Disease Models, Animal; Fasting; Fatty Acids; Linoleic Acid; Linoleic Acids; Lipid Mobilization; Lymphoma; Male; Metabolic Clearance Rate; Mice; Neoplasms, Experimental; Peptides

We had previously hypothesized that linoleic acid (LA) was essential for development of alcoholic induced liver injury in our rat model. Male Wistar rats were fed a nutritionally adequate diet (25% calories as fat) with ethanol (8-17 g/kg/day). The source of fat was tallow (0.7% LA), lard (2.5% LA) or tallow supplemented with linoleic acid (2.5%). Liver damage was followed monthly by obtaining blood for alanine aminotransferase assay and liver biopsy for assessment of morphologic changes. Enzyme and histologic changes (fatty liver, necrosis and inflammation) in the tallow-linoleic acid-ethanol fed animals were more severe than in the lard-ethanol group. The tallow ethanol group did not show any evidence of liver injury. Our results strongly support our hypothesis that LA is essential for development of alcoholic liver disease in our rat model.

Topics: Alanine Transaminase; Animals; Dietary Fats; Disease Models, Animal; Linoleic Acid; Linoleic Acids; Liver Diseases, Alcoholic; Male; Rats; Rats, Inbred Strains

Topics: Animals; Chronic Disease; Disease Models, Animal; Drug Combinations; Exocrine Pancreatic Insufficiency; Injections; Linoleic Acid; Linoleic Acids; Male; Oleic Acids; Pancreatic Ducts; Rats; Rats, Inbred Strains; Solutions; Zein

Chronic pancreatic insufficiency (CPI) was induced in male Wistar rats by the injection of a zein-oleic acid-linoleic acid solution into their pancreaticobiliary ducts. Animals injected developed severe pancreatic atrophy with fibrosis and greater than 90% loss of pancreatic enzyme content. The animals also developed malabsorption of fat and bentiromide. Three weeks after the CPI lesion was induced, animals were randomized to receive cerulein 2 micrograms/kg twice daily subcutaneously or saline twice daily subcutaneously for 2 weeks. Cerulein significantly increased pancreatic trypsinogen (p less than 0.03), amylase (p less than 0.01), lipase (p less than 0.02), DNA (p less than 0.02), and RNA (p less than 0.01) content and improved fat and bentiromide malabsorption as compared to saline (p less than 0.05). We conclude that cerulein therapy can cause significant hyperplasia of pancreatic acinar parenchyma in an animal model of CPI and that this therapy can partially reverse malabsorption.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Drug Combinations; Exocrine Pancreatic Insufficiency; Hyperplasia; Linoleic Acid; Linoleic Acids; Male; Oleic Acid; Oleic Acids; Pancreas; Rats; Rats, Inbred Strains; Zein