linoleic-acid and Atherosclerosis

Obesity and its comorbidities, including type 2 diabetes and cardiovascular disease, are straining our healthcare system, necessitating the development of novel strategies for weight loss. Lifestyle modifications, such as exercise and caloric restriction, have proven effective against obesity in the short term, yet obesity persists because of the high predilection for weight regain. Therefore, alternative approaches to achieve long term sustainable weight loss are urgently needed. Conjugated linoleic acid (CLA), a fatty acid found naturally in ruminant animal food products, has been identified as a potential anti-obesogenic agent, with substantial efficacy in mice, and modest efficacy in obese human populations. Originally described as an anti-carcinogenic fatty acid, in addition to its anti-obesogenic effects, CLA has now been shown to possess anti-atherosclerotic properties. This review summarizes the pre-clinical and human studies conducted using CLA to date, which collectively suggest that CLA has efficacy against cancer, obesity, and atherosclerosis. In addition, the potential mechanisms for the many integrative physiological effects of CLA supplementation will be discussed in detail, including an introduction to the gut microbiota as a potential mediator of CLA effects on obesity and atherosclerosis.

Topics: Atherosclerosis; Humans; Linoleic Acid; Neoplasms; Obesity

Topics: Arachidonic Acid; Atherosclerosis; Biological Evolution; Brain; Cardiovascular Diseases; Diet; Dietary Fats; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Gene Expression; Gene Expression Regulation; Genetic Variation; Humans; Inflammation; Linoleic Acid; Nutrition Policy; Nutritional Requirements; Trans Fatty Acids

Atherosclerosis, macular degeneration, and neurodegenerative diseases such as Alzheimer's disease, are associated with the intracellular accumulation of substances that impair cellular function and viability. Reversing this accumulation may be a valuable therapy, but the accumulating substances resist normal cellular catabolism. On the other hand, these substances are naturally degraded in the soil and water by microorganisms. Thus, we propose the concept of "medical bioremediation," which derives from the successful field of in situ environmental bioremediation of petroleum hydrocarbons. In environmental bioremediation, communities of microorganisms mineralize hydrophobic organics using a series of enzymes. In medical bioremediation, we hope to utilize one or several microbial enzymes to degrade the intracellular accumulators enough that they can be cleared from the affected cells. Here, we present preliminary, but promising results for the bacterial biodegradation of 7-ketocholesterol, the main accumulator of foam cells associated with atherosclerosis. In particular, we report on the isolation of several Nocardia strains able to biodegrade 7-ketocholesterol and as an ester of 7-ketocholoesterol. We also outline key intermediates in the biodegradation pathway, a key step towards identifying the key enzymes that may lead to a therapy.

Topics: Atherosclerosis; Biodegradation, Environmental; Foam Cells; Genetic Engineering; Hydrocarbons; Ketocholesterols; Linoleic Acid; Longevity; Lysosomes; Metabolism; Models, Chemical; Nocardia; Petroleum

The etiology of atherosclerosis is complex and multifactorial but there is extensive evidence indicating that oxidized lipoproteins may play a key role. At present, the site and mechanism by which lipoproteins are oxidized are not resolved, and it is not clear if oxidized lipoproteins form locally in the artery wall and/or are sequestered in atherosclerotic lesions following the uptake of circulating oxidized lipoproteins. We have been focusing our studies on demonstrating that such potentially atherogenic oxidized lipoproteins in the circulation are at least partially derived from oxidized lipids in the diet. Thus, the purpose of our work has been to determine in humans whether oxidized dietary oxidized fats such as oxidized fatty acids and oxidized cholesterol are absorbed and contribute to the pool of oxidized lipids in circulating lipoproteins. When a meal containing oxidized linoleic acid was fed to normal subjects, oxidized fatty acids were found only in the postprandial chylomicron/chylomicron remnants (CM/RM) which were cleared from circulation within 8 h. No oxidized fatty acids were detected in low density lipoprotein (LDL) or high density lipoprotein (HDL) fractions at any time. However, when alpha-epoxy cholesterol was fed to human subjects, alpha-epoxy cholesterol in serum was found in CM/RM and also in endogenous very low density lipoprotein, LDL, and HDL and remained in the circulation for 72 h. In vitro incubation of the CM/RM fraction containing alpha-epoxy cholesterol with human LDL and HDL that did not contain alpha-epoxy cholesterol resulted in a rapid transfer of oxidized cholesterol from CM/RM to both LDL and HDL. We have suggested that cholesteryl ester transfer protein is mediating the transfer. Thus, alpha-epoxy cholesterol in the diet is incorporated into CM/RM fraction and then transferred to LDL and HDL contributing to lipoprotein oxidation. We hypothesize that diet-derived oxidized fatty acids in chylomicron remnants and oxidized cholesterol in remnants and LDL accelerate atherosclerosis by increasing oxidized lipid levels in circulating LDL and chylomicron remnants. This hypothesis is supported by our feeding experiments in animals. When rabbits were fed oxidized fatty acids or oxidized cholesterol, the fatty streak lesions in the aorta were increased by 100%. Moreover, dietary oxidized cholesterol significantly increased aortic lesions in apo-E and LDL receptor-deficient mice. A typical Western diet is rich in oxidized fats

Topics: Animals; Atherosclerosis; Cholesterol, Dietary; Chylomicrons; Dietary Fats; Fatty Acids; Humans; Linoleic Acid; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Oxidation-Reduction

The cholesterol hypothesis implies that reducing the intake of saturated fatty acids and cholesterol and increasing that of polyunsaturated fatty acid are effective in lowering serum total cholesterol (TC), and thereby reducing the incidence of coronary heart disease (CHD). However, these dietary recommendations are essentially ineffective in reducing TC in the long run, but rather increase mortality rates from CHD and all causes. The reported "apparent relative risk of high TC in CHD mortality" (the ratio of mortality at the highest/lowest TC levels) varied several-fold among populations studied. The incidence of familial hypercholesterolemia (FH) in a population was proposed to be a critical factor in the observed variability, which could be accounted for by assuming that 1) the high CHD mortality rate in high-TC groups is mainly a reflection of the incidence and severity of FH, and 2) high TC is not a causative factor of CHD in non-FH cases. This interpretation is supported by recent observations that high TC is not positively associated with high CHD mortality rates among general populations more than 40-50 years of age. More importantly, higher TC values are associated with lower cancer and all-cause mortality rates among these populations, in which relative proportions of FH are likely to be low (circa 0.2%). Although the effectiveness of statins in preventing CHD has been accepted in Western countries, little benefit seems to result from efforts to limit dietary cholesterol intake or to TC values to less than approximately 260 mg/dl among the general population and the elderly. Instead, an unbalanced intake of omega6 over omega3 polyunsaturated fats favors the production of eicosanoids, the actions of which lead to the production of inflammatory and thrombotic lipid mediators and altered cellular signaling and gene expression, which are major risk factors for CHD, cancers, and shorter longevity. Based on the data reviewed here, it is urgent to change the direction of current cholesterol-related medication for the prevention of CHD, cancer, and all-cause mortality.

Topics: alpha-Linolenic Acid; Anticholesteremic Agents; Atherosclerosis; Coronary Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Inflammation; Inflammation Mediators; Linoleic Acid; Neoplasms; Risk Factors; Thrombosis

Conjugated linoleic acid (CLA) is a term used for positional and geometrical isomers of linoleic acid whose two unsaturated bonds are separated by one saturated bond (cis9trans11 and trans10cis12). Cooked meat and milk are among the richest dietary sources of CLA. Recently, much attention has been devoted to CLA due to its anti-cancer, anti-atherogenic, and anti-diabetic properties.. Our study group comprised 29 patients aged 45 to 75 years who were operated for atherosclerotic stenosis in the carotid arteries.. Venous blood was collected after an overnight fast. Total cholesterol and triglycerides were assayed with enzymatic test kits. HDL-cholesterol was measured after precipitation with sodium magnesium phosphotungstate. LDL-cholesterol was calculated from total cholesterol, triglyceride and HDL-cholesterol concentrations using Friedewald's formula. A Perkin-Elmer gas chromatograph (model 8500) was used to analyze fatty acids methyl esters. Statistical analysis was performed with the Statistica Neural Networks software. Significantly lower plasma content of c9t11 CLA, linoleic, and arachidonic acids was found in the study group as compared with controls. Parametric analysis disclosed that c9t11 CLA concentrations depended on triglycerides and arachidonic acid in the study group and on linoleic acid and triglycerides in controls. An increase in total cholesterol concentration was associated with a decrease in the concentration of c9t11 CLA in the study group and a parallel increase in the control group.

Topics: Adult; Aged; Arachidonic Acid; Atherosclerosis; Cholesterol; Female; Humans; Linoleic Acid; Male; Middle Aged; Neural Networks, Computer

Linoleic acid (LA) has a two-sided effect with regard to serum cholesterol-lowering and pro-inflammation, although whether this fatty acid reduces serum cholesterol and the development of atherosclerosis under high-cholesterol conditions has yet to be ascertained. In this study, we examine the effects of dietary LA on reducing serum cholesterol and atherosclerosis development under high-cholesterol conditions. Male and female apoE-deficient (ApoE

Topics: Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Cholesterol, Dietary; Diet; Female; Hypercholesterolemia; Inflammation; Linoleic Acid; Male; Mice; RNA, Messenger

Dietary saturate fatty acids (SFAs) have been consistently linked to atherosclerosis and obesity, both of which are characterized by chronic inflammation and impaired lipid metabolism. In comparison, the effects of linoleic acid (LA), the predominant polyunsaturated fatty acid in the Western diet, seem to diverge. Data from human studies suggest a positive association between high dietary intake of LA and the improvement of cardiovascular risk. However, excessive LA intake has been implicated in the development of obesity. Concerns have also been raised on the potential pro-inflammatory properties of LA metabolites. Herein, by utilizing a mouse model with liver-specific Ldlr knockdown, we directly determined the effects of replacing SFAs with LA in a Western diet on the development of obesity and atherosclerosis. Specifically, mice treated with a Ldlr ASO were placed on a Western diet containing either SFA-rich butter (WD-B) or LA-rich corn oil (WD-CO) for 12 weeks. Despite of showing no changes in body weight gain or adiposity, mice on WD-CO exhibited significantly less atherosclerotic lesions compared to those on WD-B diet. Reduced lesion formation in the WD-CO-fed mice corresponded with a reduction of plasma triglyceride and cholesterol content, especially in VLDL and LDL, and ApoB protein levels. Although it increased expression of proinflammatory cytokines TNF-α and IL-6 in the liver, WD-CO did not appear to affect hepatic injury or damage when compared to WD-B. Collectively, our results indicate that replacing SFAs with LA in a Western diet could reduce the development of atherosclerosis independently of obesity.

Topics: Animals; Atherosclerosis; Diet, Western; Fatty Acids; Humans; Linoleic Acid; Liver; Mice; Obesity; Receptors, LDL

Both monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) play important roles in lipid metabolism, and diets enriched with either of these two fatty acids are associated with decreased cardiovascular risk. Conventional soybean oil (CSO), a common food ingredient, predominantly contains linoleic acid (LA; C18:2), a n-6 PUFA. Recently, a modified soybean oil (MSO) enriched in oleic acid (C18:1), a n-9 MUFA, has been developed, because of its improved chemical stability to oxidation. However, the effect of the different dietary soybean oils on cardiovascular disease remains unknown. To test whether diets rich in CSO versus MSO would attenuate atherosclerosis development, LDL receptor knock-out (LDLR-KO) mice were fed a Western diet enriched in saturated fatty acids (control), or a Western diet supplemented with 5% (w/w) LA-rich CSO or high-oleic MSO for 12 weeks. Both soybean oils contained a similar amount of linolenic acid (C18:3 n-3). The CSO diet decreased plasma lipid levels and the cholesterol content of VLDL and LDL by approximately 18% (p < 0.05), likely from increased hepatic levels of PUFA, which favorably regulated genes involved in cholesterol metabolism. The MSO diet, but not the CSO diet, suppressed atherosclerotic plaque size compared to the Western control diet (Control Western diet: 6.5 ± 0.9%; CSO diet: 6.4 ± 0.7%; MSO diet: 4.0 ± 0.5%) (p < 0.05), independent of plasma lipid level changes. The MSO diet also decreased the ratio of n-6/n-3 PUFA in the liver (Control Western diet: 4.5 ± 0.2; CSO diet: 6.1 ± 0.2; MSO diet: 2.9 ± 0.2) (p < 0.05), which correlated with favorable hepatic gene expression changes in lipid metabolism and markers of systemic inflammation. In conclusion, supplementation of the Western diet with MSO, but not CSO, reduced atherosclerosis development in LDLR-KO mice independent of changes in plasma lipids.

Topics: Animals; Atherosclerosis; Cholesterol; Dietary Supplements; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Linoleic Acid; Mice; Mice, Knockout; Oleic Acid; Receptors, LDL; Soybean Oil

This study aims to investigate the compatibility mechanism of Trichosanthis Fructus-Allii Macrostemonis Bulbus combination against atherosclerosis(AS) in apolipoprotein E-deficient(ApoE~(-/-)) mice. To be specific, high-fat diet was used to induce AS in mice. The pathological morphology of mice aorta was evaluated based on hematoxylin-eosin(HE) staining and Masson staining. The metabolic profiling of mouse serum samples was performed with ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Multiple statistical analysis methods including partial least squares-discriminant analysis and orthogonal partial least squares-discriminant analysis were employed to screen potential biomarkers in mice. With the techniques in network pharmacology, the metabolites related to AS and the targets in the metabolic pathways were screened out. The results showed that Trichosanthis Fructus alone and the pair all reduced the plaque area of aortic sinus(P<0.05) and collagen area(P<0.05). Compared with the Trichosanthis Fructus alone and Allii Macrostemonis Bulbus alone, the combination significantly decreased the plaque area of aortic sinus(P<0.05) and collagen area(P<0.05). Metabolomics revealed 16 biomarkers in mice. Trichosanthis Fructus re-gulated the abnormal levels of 4 metabolites in glycerophosphatide metabolic pathway. Allii Macrostemonis Bulbus modulated the abnormal levels of 2 metabolites in arachidonic acid metabolic pathway and the combination recovered the levels of 8 metabolites in glycerophosphatide, linoleic acid, arachidonic acid, and pyrimidine metabolic pathways. Network pharmacology suggested that Trichosanthis Fructus regulated 24 targets which related to 2 AS-associated metabolites and involved glycerophosphatide metabolic pathway. Allii Macroste-monis Bulbus modulated 40 targets which related to 2 AS-associated metabolites and involved the arachidonic acid metabolic pathway. The combination regulated 57 targets which related to 6 AS-metabolites and involved linoleic acid metabolic pathway, glycerophosphatide metabolic pathway, and arachidonic acid metabolic pathway. These results indicate that the Trichosanthis Fructus-Allii Macrostemonis Bulbus combination enhances the regulation of linoleic acid metabolism, glycerophosphatide metabolism, and arachido-nic acid metabolism, thereby synergistically alleviating lipid disorder and inflammatory response in AS mice.

Topics: Animals; Arachidonic Acid; Atherosclerosis; Biomarkers; Drugs, Chinese Herbal; Linoleic Acid; Metabolomics; Mice; Network Pharmacology

Topics: Animals; Atherosclerosis; Carrier Proteins; CD36 Antigens; Cholesterol; Cholesterol, HDL; Gene Expression; Hypercholesterolemia; Linoleic Acid; Liver; Scavenger Receptors, Class B; Xestospongia

Topics: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Brachial Artery; Carotid Artery, Common; Carotid Intima-Media Thickness; Dilatation; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Female; Humans; Linoleic Acid; Male; Regional Blood Flow; Risk Factors; Ultrasonography

Not all obese individuals develop cardiovascular disease (CVD). Hyperaldosteronism is suggested to cause inflammation and metabolic dysregulation, and might contribute to CVD development in obese individuals.. We aimed to investigate the association of aldosterone concentrations with inflammation, metabolic disturbances, and atherosclerosis in overweight and obese individuals. Additionally, we measured renin concentrations to investigate whether the observed effects reflected general activation of the renin-angiotensin-aldosterone system (RAAS).. A cross-sectional cohort study (300-OB study) was conducted. Various inflammatory parameters, traits of the metabolic syndrome, lipidome and metabolome parameters, fat distribution, and carotid atherosclerosis were associated with plasma aldosterone and renin levels.. The setting of this study was the Radboudumc (i.o. Radboudumc), the Netherlands.. A total of 302 individuals with a body mass index greater than or equal to 27 kg/m2 participated.. Aldosterone was associated with various markers of inflammation and metabolic dysregulation, which partly differed from the associations observed for renin. Although both were associated with inflammatory cell numbers, only renin was associated with classical markers of systemic inflammation. Both were associated with the metabolic syndrome and hepatic steatosis. Of the traits that constitute metabolic syndrome, aldosterone, but not renin, was associated with triglyceride concentrations. Accordingly, aldosterone was associated with large very low-density lipoprotein particles; metabolomics studies further associated aldosterone with urate concentrations and derivatives of the linoleic acid metabolism pathway. Neither aldosterone nor renin was associated with atherosclerotic plaque thickness.. Aldosterone is not an important driver of systemic inflammation in the obese, whereas aldosterone concentrations and metabolic dysregulation are strongly intertwined in these individuals. Although prospective studies are necessary to validate these results, the independent effects of aldosterone on carotid atherosclerosis appear modest.

Topics: Aged; Aged, 80 and over; Aldosterone; Atherosclerosis; Biomarkers; Carotid Arteries; Cross-Sectional Studies; Fasting; Female; Humans; Hyperaldosteronism; Inflammation; Linoleic Acid; Lipoproteins, VLDL; Magnetic Resonance Imaging; Male; Metabolic Syndrome; Metabolomics; Middle Aged; Netherlands; Obesity; Renin; Triglycerides

Endothelial cell activation and dysfunction could lead to endothelial injury that is an important factor in the development of vascular diseases. Vascular injury is strongly associated with disturbed endothelial cell energetics and pyridine nucleotide pool. This study aimed to evaluate the effects of inflammatory stimuli (IL-6, LPS), uric acid, hyperglycemia, fatty acids, flavonoids, statins and nonsteroidal anti-inflammatory drugs on cellular concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and nicotinamide adenine dinucleotide (NAD

Topics: Adenosine Triphosphate; Animals; Atherosclerosis; Atorvastatin; Blood Vessels; Cell Line; Cytokines; Docosahexaenoic Acids; Endothelial Cells; Fatty Acids, Unsaturated; Kaempferols; Linoleic Acid; Mice; NAD; Nucleotides; Palmitic Acid; Pyridines

Among unsaturated fatty acids, epidemiologic studies have demonstrated that ω-6 (linoleic acid) and ω-3 (linolenic acid) fatty acids show different associations with risk of cardiovascular disease (CVD), although its molecular mechanisms remain unclear. To determine why consumption of ω-3 fatty acid is associated with lower risk of CVD, we investigated the biological functions of ω-6 (linoleic acid) and ω-3 (linolenic acid) in reconstituted HDL (rHDL) after encapsulation using human cells and zebrafish embryo. Apolipoprotein A-I (apoA-I) is the principal protein behind the beneficial functions of HDL, which include potent anti-oxidant, anti-inflammatory, and anti-atherosclerotic activities in blood. Several rHDLs were synthesized with apoA-I and different molar ratio of ω-6 or ω-3 fatty acid. Both fatty acids showed similar solubility in rHDL up to a molar ratio of 95:5:1:10 (palmitoyloleoyl phosphatidylcholine:cholesterol:apoA-I:fatty acid). Although both rHDL showed similar structural properties and α-helical contents, ω-6-rHDL showed loss of anti-oxidant ability against LDL oxidation. Uptake of acetylated LDL into macrophages was inhibited by ω-3-rHDL but not ω-6-rHDL, suggesting that ω-6-rHDL has higher pro-atherosclerotic activity. ω-3-rHDL showed more enhanced cholesterol efflux activity with less accumulation of triglyceride in the macrophage. ω-6-rHDL caused more senescence in human dermal fibroblast cells with cytotoxicity, while ω-3-rHDL treatment inhibited the senescence. In zebrafish embryo survivability, ω-3-rHDL-injected embryos showed 86±3% survival, whereas ω-6-rHDL-injected ones showed 72±2% survival as well as an elevated inflammatory response in zebrafish embryos. In conclusion, ω-6-rHDL and ω-3-rHDL show different physiological activities in atherosclerosis, inflammation, and cellular senescence.

Topics: alpha-Linolenic Acid; Animals; Antioxidants; Apolipoprotein A-I; Atherosclerosis; Cellular Senescence; Circular Dichroism; Fibroblasts; Gene Expression Regulation, Developmental; Humans; Inflammation; Linoleic Acid; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Macrophages; Oxygen; Phagocytosis; Reactive Oxygen Species; Tryptophan; Zebrafish

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for CVD and has been proposed as a marker of vascular inflammation. Polyunsaturated n-3 fatty acids (FA) and several n-6 FA are known to suppress inflammation and may influence Lp-PLA2 mass and activity. The associations of n-3 and n-6 plasma FA with Lp-PLA2 mass and activity were analysed using linear regression analysis in 2246 participants of the Multi-Ethnic Study of Atherosclerosis; statistical adjustments were made to control for body mass, inflammation, lipids, diabetes, and additional clinical and demographic factors. Lp-PLA2 mass and activity were significantly lower in participants with the higher n-3 FA EPA (β = - 4·72, P< 0·001; β = - 1·53; P= 0·023) and DHA levels (β = - 4·47, β = - 1·87; both P< 0·001). Those in the highest quintiles of plasma EPA and DHA showed 12·71 and 19·15 ng/ml lower Lp-PLA2 mass and 5·7 and 8·90 nmol/min per ml lower Lp-PLA2 activity than those in the first quintiles, respectively. In addition, lower Lp-PLA2 mass and activity were associated with higher levels of n-6 arachidonic acid (β = - 1·63, β = - 1·30; both P< 0·001), while γ-linolenic acid was negatively associated with activity (β = - 27·7, P= 0·027). Lp-PLA2 mass was significantly higher in participants with greater plasma levels of n-6 linoleic (β = 0·828, P= 0·011) and dihomo-γ-linolenic acids (β = 4·17, P= 0·002). Based on their independent associations with Lp-PLA2 mass and activity, certain n-3 and n-6 FA may have additional influences on CVD risk. Intervention studies are warranted to assess whether these macronutrients may directly influence Lp-PLA2 expression or activity.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Aged; Atherosclerosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; gamma-Linolenic Acid; Humans; Inflammation; Linoleic Acid; Male; Middle Aged; Regression Analysis; Risk Factors

Polyunsaturated fatty acids (PUFAs) have positive effect on the regulation of plasma lipids. But the mechanism for them to modulate lipid homeostasis in macrophage is still unclear. In this study, we employed PUFA to pretreat macrophages and evaluated the variations of lipid droplet (LD) content, lipid composition, and expressions of LD-associated genes in macrophage-derived foam cells.. THP-1-derived macrophages or human peripheral blood monocyte-derived macrophages were pre-treated with four non-esterified fatty acids (NEFAs) separately: saturated fatty acid (SFA)-palmitic acid (PA), monounsaturated fatty acids (MUFAs)-oleic acid (OA), PUFAs-linoleic acid (LA) and eicosapentaenoic acid (EPA). Intracellular lipid content and cholesterol efflux were analyzed in THP-1 macrophage-derived foam cells. Related gene expressions were detected by quantitative real-time PCR.. PUFA pre-treatment reduced cholesterol content in foam cells and increased cholesterol efflux to lipid-free apoAI in conditioned medium compared with PA or OA group. Cell death-inducing DFF45 like effector (CIDE) and Perilipin-Adipophilin-TIP47 (PAT) family members, as LD-associated proteins, showed specific gene expression profiles after PUFA pre-treatment. These results may help to explain the process of lipid metabolism within foam cells.. PUFA (LA or EPA) had a potential protective effect against cholesterol accumulation. The specific expressions of CIDE and PAT genes may provide clues to explore the protective mechanism of PUFA in foam cells.

Topics: Acyltransferases; Apoptosis Regulatory Proteins; Atherosclerosis; Cell Line; Cell Survival; Cholesterol; Eicosapentaenoic Acid; Foam Cells; Humans; Linoleic Acid; Lipids; Macrophages; Oleic Acid; Palmitic Acid; Transcriptome

S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knockdown of HO-1 reversed only the SAM-induced preventive effect of cell apoptosis. The LA-induced HO-1 expression was dependent on PPARα, whereas SAM induced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFDfed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was responsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis.

Topics: Animals; Apoptosis; Atherosclerosis; Cells, Cultured; Diet, High-Fat; Endothelial Cells; Endothelium, Vascular; Enzyme Induction; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Linoleic Acid; Male; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; S-Adenosylmethionine; Stress, Physiological

Dysfunction of endothelial cells and activation of monocytes in the vascular wall are important pathogenetic factors of atherosclerosis. Conjugated linoleic acids (CLAs) can modulate the function of immune system in humans: reduce the concentration of atherogenic lipoproteins, and the intensity of inflammatory processes in the plasma. In this paper, we focus on macrophage's surface integrins (β1 integrin CD49d/CD29-(VLA4); Mac-1 as well as endothelial human vein endothelial cell (HUVEC) surface adhesins: vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1)) expression in relation to CLA isomer used during cell culture. Both CLA isomers decreased expression of VLA-4 and Mac-1 on macrophages compared with control cells (cultured with bovine serum albumine (BSA) or oxidized form of low-density lipoproteins). cis-9, trans-11 CLA isomer reduced ICAM-1 and VCAM-1 expression on the endothelium surface. Strong tendency to reduce of adhesion of macrophages to HUVEC in the cells cultured with CLA isomers was observed. The potential role of cis-9, trans-11 CLA in the reduction of adhesion of macrophages to the HUVEC--one of the important steps in the inflammatory process, can be considerate. These mechanisms may contribute to the potent anti-atherosclerotic effects of CLA in vivo.

Topics: Animals; Atherosclerosis; Cattle; Cell Adhesion; Cell Culture Techniques; Dietary Fats; Endothelial Cells; Endothelium, Vascular; Humans; Inflammation; Integrin alpha4beta1; Intercellular Adhesion Molecule-1; Isomerism; Linoleic Acid; Linoleic Acids, Conjugated; Lipoproteins, LDL; Macrophage-1 Antigen; Macrophages; Serum Albumin; Umbilical Veins; Vascular Cell Adhesion Molecule-1

Systemic inflammation is a well-known risk factor for diseases such as atherosclerosis and is augmented by the presence of obesity. In addition, it has been shown that inflammation may be negatively influenced by certain macronutrients, specifically the omega-3 and omega-6 fatty acids. The primary aim of this study is to determine whether obesity modifies the association between plasma phospholipid polyunsaturated fatty acids (PUFAs) and markers of inflammation and endothelial activation in Multi-Ethnic Study of Atherosclerosis (MESA) participants.. A sample of 2848 adults (25% African American, Chinese, Hispanic, and White) randomly selected from the MESA cohort.. Relative plasma PUFA concentrations were determined using gas chromatography-flame ionization detection. Levels of three inflammatory markers (high-sensitivity C-reactive protein, interleukin (IL)-6 and tumor necrosis factor-receptor 1) and two endothelial activation markers (soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin) were determined with enzyme immunoassays. Linear regression analysis was used to evaluate the relationship between these markers and plasma PUFAs.. Obesity modified the associations of linoleic acid (P(int)=0.01), dihomo-γ-linolenic (P(int)=0.07) and eicosapentaenoic acid (EPA) (P(int)=0.04) with sICAM-1 concentrations; in addition, obesity modified the association of IL-6 with dihomo-γ-linolenic (P(int)=0.01). In obese individuals, sICAM-1 was inversely related to EPA levels (P=0.02), but directly related to linoleic acid levels (P<0.001). Conversely, sICAM-1 was inversely related to linoleic acid levels in normal weight individuals (P=0.04). IL-6 concentrations were significantly and directly related to dihomo-γ-linolenic acid (DGLA) in normal weight (P=0.01) and obese participants (P<0.001), but the scale of increase across tertiles was greater in obese adults. Main effects of fatty acid and inflammatory marker associations are also reported.. The modifying effect of obesity on the association of plasma PUFAs with IL-6 and sICAM-1 suggests differences in fatty acid metabolism and may also have implications in dietary fatty acid intake for obese individuals, particularly for linoleic and EPAs. Further study is warranted to confirm and explain the strong associations of DGLA with inflammatory and endothelial activation markers.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; C-Reactive Protein; Cohort Studies; Disease Progression; E-Selectin; Endothelium, Vascular; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Linear Models; Linoleic Acid; Male; Middle Aged; Obesity

The objective of the study was to determine the effects of oxidized linoleic acid (Ox-LA) on plasma leptin and to determine the relationship between plasma leptin levels and atherosclerosis in animals treated with Ox-LA. Low-density lipoprotein (LDL) receptor knockout (LDL r(-/-)) mice were fed a high fat diet with or without Ox-LA for 11 weeks. Plasma leptin levels in the high fat group consuming Ox-LA were significantly higher (14,052 ± 601 pg/mL vs. 10,950 ± 541 pg/mL; P < .01) compared to the group receiving the high fat diet alone. There was a highly significant correlation between the plasma leptin levels and aortic atherosclerotic lesions. From this we conclude that chronic exposure to dietary Ox-LA increases the plasma levels of leptin in LDL r(-/-) mice on a high fat diet. Considering our previous finding that dietary Ox-LA increased atherosclerosis, the current findings emphasize the need to reduce dietary intake of oxidized fat.

Topics: Animals; Aorta; Atherosclerosis; Cholesterol, Dietary; Cholesterol, LDL; Leptin; Linoleic Acid; Lipid Peroxidation; Lipoproteins, LDL; Male; Mice; Mice, Knockout; Obesity; Oxidative Stress; Receptors, LDL; Triglycerides

Spectroscopy-based approaches can provide an insight into the biochemical composition of a tissue sample. In the present work Fourier transform infrared (FT-IR) spectroscopy was used to develop a reliable methodology to study the content of free fatty acids, triglycerides, cholesteryl esters as well as cholesterol in aorta from mice with atherosclerosis (ApoE/LDLR(-/-) mice). In particular, distribution and concentration of palmitic, oleic and linoleic acid derivatives were analyzed. Spectral analysis of pure compounds allowed for clear discrimination between free fatty acids and other similar moieties based on the carbonyl band position (1699-1710 cm(-1) range). In order to distinguish cholesteryl esters from triglycerides a ratio of carbonyl band to signal at 1010 cm(-1) was used. Imaging of lipids in atherosclerotic aortic lesions in ApoE/LDLR(-/-) mice was followed by Hierarchical Cluster Analysis (HCA). The aorta from C57Bl/6J control mice (fed with chow diet) was used for comparison. The measurements were completed with an FT-IR spectrometer equipped with a 128 × 128 FPA detector. In cross-section of aorta from ApoE/LDLR(-/-) mice a region of atherosclerotic plaque was clearly identified by HCA, which was later divided into 2 sub-regions, one characterized by the higher content of cholesterol, while the other by higher contents of cholesteryl esters. HCA of tissues deposited on normal microscopic glass, hence limited to the 2200-3800 cm(-1) spectral range, also identified a region of atherosclerotic plaque. Importantly, this region correlates with the area stained by standard histological staining for atherosclerotic plaque (Oil Red O). In conclusion, the use of FT-IR and HCA may provide a novel tool for qualitative and quantitative analysis of contents and distribution of lipids in atherosclerotic plaque.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol Esters; Cluster Analysis; Diagnostic Imaging; Female; Linoleic Acid; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Oleic Acid; Palmitates; Receptors, LDL; Spectroscopy, Fourier Transform Infrared; Triglycerides

In this study, a series of small molecule inhibitors of human FABP4 were identified through virtual screening. Compound 1 is the most potent hit against FABP4 with a selectivity of more than 144-fold preferences over human FABP3. In addition, MD simulation and mutation studies revealed key residues for inhibitory potency and selectivity, which provides a guideline for further drug design against obesity, diabetes and atherosclerosis.

Topics: Atherosclerosis; Binding Sites; Computer Simulation; Diabetes Mellitus; Drug Discovery; Drug Evaluation, Preclinical; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Humans; Mutation; Obesity; Organic Chemicals; Protein Binding; Structure-Activity Relationship; Substrate Specificity

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of oxidized lipids in arterial lesions. Recently we studied the degradation of peroxidized linoleic acid and suggested that oxidation is an essential process that results in the generation of terminal products, namely mono- and dicarboxylic acids that may lack the pro-atherogenic effects of peroxidized lipids. In continuation of that study, we tested the effects of azelaic acid (AzA), one of the end products of linoleic acid peroxidation, on the development of atherosclerosis using low density lipoprotein receptor knockout (LDLr(-/-)) mice.. LDLr(-/-) mice were fed with a high fat and high cholesterol Western diet (WD group). Another group of animals were fed the same diet with AzA supplementation (WD+AzA group). After 4 months of feeding, mice were sacrificed and atherosclerotic lesions were measured. The results showed that the average lesion area in WD+AzA group was 38% (p<0.001) less as compared to WD group. The athero-protective effect of AzA was not related to changes in plasma lipid content. AzA supplementation decreased the level of CD68 macrophage marker by 34% (p<0.05).. The finding that AzA exhibits an anti-atherogenic effect suggests that oxidation of lipid peroxidation-derived aldehydes into carboxylic acids could be an important step in the body's defense against oxidative damage.

Topics: Animals; Atherosclerosis; Dicarboxylic Acids; Female; Linoleic Acid; Lipid Peroxidation; Mice; Mice, Knockout; Receptors, LDL

Enhanced oxidative stress is implicated in the development of atherosclerosis in humans and animal models. F(2)-isoprostanes are formed in vivo via free radical peroxidation of arachidonic acid, and their quantification has allowed assessment of oxidative stress in vivo. F(2)-isoprostanes associate with lipids, although their distribution in human plasma lipoproteins is unknown. Our aim was to determine the distribution and levels of F(2)-isoprostanes in lipoproteins isolated from human plasma by ultracentrifugation and fast protein liquid chromatography (FPLC). F(2)-isoprostanes were significantly higher in HDL compared with LDL or VLDL after isolation by ultracentrifugation or FPLC. Furthermore, HDL3 particles contained elevated levels of F(2)-isoprostanes compared with HDL2. Platelet activating factor acetylhydrolase (PAF-AH), which hydrolyses esterified F(2)-isoprostanes from phospholipids, was predominantly associated with LDL. Reduced F(2)-isoprostanes in LDL may be related to higher PAF-AH activity in LDL. Paraoxonase 1 (PON-1) activity was associated with HDL2 and may be a contributing factor to the lower F(2)-isoprostanes in HDL2 compared with HDL3. Further studies are required to establish the implications of these findings on HDL function.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Amidines; Arachidonic Acid; Aryldialkylphosphatase; Atherosclerosis; Biological Transport, Active; Carrier Proteins; F2-Isoprostanes; Female; Humans; In Vitro Techniques; Linoleic Acid; Lipid Peroxides; Lipoproteins; Lipoproteins, HDL; Male; Oxidants

The bulk of LDL entrapped in the arterial intima is modified by hydrolytic enzymes, leading to extensive cleavage of cholesterylesters and liberation of fatty acids. The latter induce apoptosis in endothelial cells but are far less cytotoxic towards macrophages. We have compared the cytotoxic effects of enzymatically modified LDL (E-LDL) on macrophages and polymorphonuclear granulocytes (PMN).. E-LDL displayed toxicity towards PMN at far lower concentrations than towards monocyte-derived macrophages. Native or oxidized LDL had no effect. Free fatty acids contained in E-LDL were the cause of the observed toxicity, which could be mimicked by linoleic acid, oleic acid and arachidonic acid. E-LDL provoked Ca(2+) influx and activated PMN, as witnessed by the generation of superoxide anions and peroxidase secretion. Inhibition of either oxidative burst or calcium influx did not diminish the cytotoxicity of E-LDL. Similar to free linoleic acid, E-LDL lysed red blood cells and rapidly rendered cells permeable to propidium iodide.. Possibly through their capacity to directly perturb cell membranes, free fatty acids contained in E-LDL exert potent cytotoxic effects on PMN. This may be one reason why PMN are not abundantly present in atherosclerotic lesions, and why PMN-depletion suppresses atherogenesis.

Topics: Adenosine Triphosphate; Animals; Arachidonic Acid; Atherosclerosis; Calcium; Cell Death; Cell Membrane Permeability; Cell Survival; Cells, Cultured; Fatty Acids, Nonesterified; Hemolysis; Humans; Hydrolysis; L-Lactate Dehydrogenase; Linoleic Acid; Lipoproteins, LDL; Macrophages; Neutrophils; Oleic Acid; Peptide Hydrolases; Peroxidase; Rabbits; Respiratory Burst; Sterol Esterase; Superoxides; Time Factors

Previously we have shown that intestinal cells efficiently take up oxidized fatty acids (OxFAs) and that atherosclerosis is increased when animals are fed a high cholesterol diet in the presence of oxidized linoleic acid. Interestingly, we found that in the absence of dietary cholesterol, the oxidized fatty acid fed low-density lipoprotein (LDL) receptor negative mice appeared to have lower plasma triglyceride (TG) levels as compared to animals fed oleic acid. In the present study, we fed C57BL6 mice a normal mice diet supplemented with oleic acid or oxidized linoleic acid (at 18 mg/animal/day) for 2 weeks. After the mice were sacrificed, we measured the plasma lipids and collected livers for the isolation of RNA. The results showed that while there were no significant changes in the levels of total cholesterol and high-density lipoprotein cholesterol (HDLc), there was a significant decrease (41.14%) in the levels of plasma TG in the mice that were fed oxidized fatty acids. The decreases in plasma TG levels were accompanied by significant increases (P<0.001) in the expressions of APOA5 and acetyl-CoA oxidase genes as well as a significant (P<0.04) decrease in APOClll gene expression. Oxidized lipids have been suggested to be ligands for peroxisome proliferator-activated receptor (PPAR*). However, there were no increases in the mRNA or protein levels of PPAR* in the oxidized linoleic acid fed animals. These results suggest that oxidized fatty acids may act through an APOA5/APOClll mechanism that contributes to lowering of TG levels other than PPAR* induction.

Topics: Animals; Apolipoprotein A-V; Apolipoprotein C-III; Apolipoproteins; Atherosclerosis; Cholesterol; Diet; Fatty Acids; Inflammation; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Oxygen; PPAR alpha; Triglycerides

Atherosclerosis is characterized by extensive thickening of the arterial intima partially resulting from deposition of collagen by vascular smooth muscle cells (SMCs). Polyunsaturated fatty acids stimulate collagen formation through NF-kappaB activation.. The present study aimed to explore the effect of conjugated linoleic acids (CLAs) which are known to inhibit NF-kappaB activation on collagen formation by SMCs.. Vascular SMCs were cultured with 50 micromol/l of CLA isomers (c9t11-CLA, t10c12-CLA) or linoleic acid (LA) and analysed for collagen formation and NF-kappaB p50 transactivation.. Treatment with CLA isomers but not LA significantly reduced PDGF-stimulated [(3)H] proline incorporation into cell layer protein of SMCs without altering cell proliferation. Simultaneous treatment with the PPARgamma inhibitor T0070907 abrogated this effect. Treatment of SMCs with c9t11-CLA and t10c12-CLA significantly reduced PDGF-induced NF-kappaB p50 activation.. CLA isomers inhibit PDGF-stimulated collagen production by vascular SMCs, which is considered to be a hallmark of atherosclerosis, in a PPARgamma-dependent manner. Whether inhibition of the NF-kappaB-pathway is of significance for the reduction of collagen formation by CLA isomers needs further investigation.

Topics: Analysis of Variance; Atherosclerosis; Benzamides; Cell Division; Cell Survival; Cells, Cultured; Collagen; Humans; Isomerism; Linoleic Acid; Linoleic Acids, Conjugated; Muscle, Smooth, Vascular; NF-kappa B; Platelet-Derived Growth Factor; PPAR gamma; Pyridines

Topics: Adult; Aged; Animals; Atherosclerosis; Cholesterol, LDL; Coronary Disease; Denmark; Dietary Fats; Eicosanoids; Endothelium, Vascular; Energy Metabolism; Fatty Acids; Fatty Acids, Nonesterified; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Fish Oils; Gene Expression Regulation; Greenland; Health Surveys; Humans; Hyperlipidemias; Inflammation; Linoleic Acid; Male; Middle Aged; Nurses; Triglycerides; United States

The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein.. hASMC exposed for 72 hours to high concentrations (800 micromol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPARgamma agonist rosiglitazone (10 micromol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity.. The response of hASMC to NEFA could induce extracellular matrix alterations favoring apoB lipoprotein deposition and atherogenesis.

Topics: Arteries; Atherosclerosis; Cells, Cultured; Chondroitin Sulfate Proteoglycans; Dyslipidemias; Glycosyltransferases; Humans; Hypoglycemic Agents; Insulin; Lectins, C-Type; Linoleic Acid; Lipoproteins, LDL; Muscle, Smooth, Vascular; Palmitates; Proteoglycans; RNA, Messenger; Sulfates; Sulfotransferases; Triglycerides; Versicans

We have conducted molecular dynamics simulations to gain insight into the atomic-scale properties of an isotropic system of cholesteryl oleate (CO) molecules. Cholesteryl esters are major constituents of low density lipoprotein particles, the key players in the formation of atherosclerosis, as well as the storage form of cholesterol. Here the aim is to clarify structural and dynamical properties of CO molecules under conditions, which are suggestive of those in the core of low density lipoprotein particles. The simulations in the fluid phase indicate that the system of CO molecules is characterized by an absence of translational order, as expected, while the orientational order between distinct CO molecules is significant at short distances, persisting over a molecular size. As for intramolecular properties, the bonds along the oleate chain are observed to be weakly ordered with respect to the sterol structure, unlike the bonds along the short hydrocarbon chain of cholesterol where the ordering is significant. The orientational distribution of the oleate chain as a whole with respect to the sterol moiety is of broad nature, having a major amount of extended and a less considerable proportion of bended structures. Distinct transient peaks at specific angles also appear. The diffusion of CO molecules is found to be a slow process and characterized by a diffusion coefficient of the order of 2x10(-9) cm2/s. This is considerably slower than diffusion, e.g., in ordered domains of lipid membranes rich in sphingomyelin and cholesterol. Analysis of the rotational diffusion rates and trans-to-gauche transition rates yield results consistent with experiments.

Topics: Atherosclerosis; Biophysics; Carbon; Carbon Monoxide; Cholesterol; Cholesterol Esters; Diffusion; Humans; Hydrocarbons; Linoleic Acid; Lipoproteins; Lipoproteins, LDL; Magnetic Resonance Spectroscopy; Models, Chemical; Models, Molecular; Models, Statistical; Models, Theoretical; Neutrons; Protein Conformation; Software; Sterols; Time Factors; X-Ray Diffraction

Recent genetic data in mouse and humans suggest that the chemokine receptors CCR2 and CX3CR1 are involved in atherogenesis; however, detailed molecular and cellular mechanisms have not been fully delineated.. Here, we show that oxidized linoleic acid metabolites, which are components of oxidized LDL found in large amounts in atherosclerotic plaque, were able to specifically induce differentiation of human monocytes to macrophages with decreased expression of CCR2, confirming a previous report, and increased expression of CX3CR1. These macrophages acquired the ability to adhere to coronary artery smooth muscle cells. The adhesion was mediated directly and predominantly by CX3CR1. Reciprocal effects of these lipids on CCR2 and CX3CR1 expression were mediated by the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma, and targeting the PPARgamma gene with sRNAi dramatically reduced macrophage adhesion to coronary artery smooth muscle cells.. These data suggest that in atherogenesis oxidized lipid-driven activation of macrophage PPARgamma in the intima may result in a proadhesive chemokine receptor switch-CCR2 off, CX3CR1 on-causing cessation of CCR2-dependent migration and activation of CX3CR1-dependent retention mechanisms, which together promote macrophage accumulation in vessel wall. Our results may explain at the molecular and cell biology levels the genetic link between CX3CR1 and atherosclerosis. Moreover, they identify macrophage binding to coronary artery smooth muscle cells as the first primary cell setting in which CX3CR1 functions as the major adhesion system.

Topics: Atherosclerosis; Cell Adhesion; Cell Differentiation; Cells, Cultured; Coronary Vessels; Flow Cytometry; Humans; Linoleic Acid; Lipoproteins, LDL; Macrophage Activation; Macrophages; Monocytes; Muscle, Smooth, Vascular; PPAR gamma; Receptors, CCR2; Receptors, Chemokine; Receptors, Interleukin-8A; RNA, Messenger

Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.

Topics: Animal Feed; Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Blotting, Western; Body Composition; Body Weight; Cytosol; Diet; Fatty Acids; Genetic Linkage; Glucose; HSP70 Heat-Shock Proteins; Inflammation; Insulin; Insulin Resistance; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Male; Mice; Mice, Knockout; Oxygen; Perfusion; Principal Component Analysis; Proteomics; Systems Biology; Triglycerides

Abnormal high density lipoprotein (HDL) metabolism among patients with diabetes and insulin resistance may contribute to their increased risk of atherosclerosis. ATP-binding cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis. Unsaturated fatty acids, which are elevated in diabetes, impair the ABCA1 pathway in cultured cells by destabilizing ABCA1 protein. Here we examined the cellular pathway that mediates the ABCA1 destabilizing effects of fatty acids. The long-chain acyl-CoA synthetase inhibitor triacsin C completely reversed fatty acid-induced ABCA1 destabilization, indicating that fatty acids need to be activated to their CoA derivatives to enhance ABCA1 degradation. Unsaturated but not saturated fatty acids stimulated phospholipase D (PLD) activity, the PLD inhibitor 1-butanol prevented the unsaturated fatty acid-induced reduction in ABCA1 levels, and the PLD2 activator mastoparan markedly reduced ABCA1 protein levels, implicating a role for PLD2 in the ABCA1 destabilizing effects of fatty acids. Unsaturated fatty acids and mastoparan increased phosphorylation of ABCA1 serines. PLD2 small interfering RNA abolished the ability of unsaturated fatty acids to inhibit lipid transport activity, to reduce protein levels, and to increase serine phosphorylation of ABCA1. The diacylglycerol analog oleoylacetylglycerol also reduced ABCA1 protein levels and increased its serine phosphorylation, suggesting that PLD2-generated diacylglycerols promote the destabilizing phosphorylation of ABCA1. These data provide evidence that intracellular unsaturated acyl-CoA derivatives destabilize ABCA1 by activating a PLD2 signaling pathway.

Topics: 1-Butanol; Animals; Apolipoproteins; Atherosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Cell Line; Cricetinae; Diglycerides; Fatty Acids; Fatty Acids, Unsaturated; Humans; Immunoblotting; Linoleic Acid; Lipids; Lipoproteins, HDL; Mice; Models, Biological; Phospholipase D; Phosphorylation; RNA, Small Interfering; Serine; Signal Transduction; Time Factors; Triazenes

The relative benefit of replacing saturated fatty acid with linoleic acids is still being debated because a linoleic acid-enriched diet increases oxidative and inflammatory stresses, although it is associated with a reduction in serum cholesterol levels. The present study was conducted to evaluate the effect of dietary supplementation of linoleic acid-rich (HL) fat, compared with a saturated fatty acid-rich (SF) fat on atherosclerotic lesion areas, serum and liver cholesterol levels, oxidative stress (urinary isoprostanes and serum malondialdehayde) and inflammatory stress (expression of aortic monocyte chemoattractant protein-1; MCP-1) in apo E-deficient mice. Male and female apo E-deficient mice (8 weeks old; seven to eight per group) were fed an AIN-76-based diet containing SF fat (50 g palm oil and 50 g lard/kg) or HL fat (100 g high-linoleic safflower-seed oil/kg) for 9 weeks. Compared with the SF diet, the HL diet lowered atherosclerosis (P<0.05). It reduced serum total cholesterol levels (P<0.05), increased HDL-cholesterol levels (P<0.05) and lowered liver esterified cholesterol levels (P<0.01). The HL diet-fed mice showed increased expression of MCP-1 mRNA (P<0.05), serum levels of malondialdehayde (P<0.05) and urinary excretion of 2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2alpha; P<0.05). These results suggest that having biomarkers in vivo for oxidative stress and inflammatory status of endothelial cells does not necessarily indicate predisposition to an increased lesion area in the aortic root in apo E-deficient mice fed an HL or SF diet.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Biomarkers; Chemokine CCL2; Cholesterol; Dietary Fats; Dietary Supplements; Dinoprost; Endothelial Cells; Fatty Acids; Female; Linoleic Acid; Liver; Male; Mice; Oxidative Stress; RNA, Messenger; Thiobarbituric Acid Reactive Substances; Vasoconstrictor Agents

Topics: Animals; Arteriosclerosis; Atherosclerosis; Cholesterol; Diet; Diet, Atherogenic; Linoleic Acid; Linoleic Acids; Lipid Metabolism; Pathology; Pharmacology; Rabbits; Research

Topics: Animals; Atherosclerosis; Cholesterol; Chromatography; Diet; Diet, Atherogenic; Dietary Fats; Environment; Fatty Acids, Unsaturated; Linoleic Acid; Lipids; Oils; Poultry; Research

Topics: Aorta; Arteriosclerosis; Atherosclerosis; Carbon Isotopes; Cholesterol; Cholesterol Esters; Linoleic Acid; Lipid Metabolism; Liver; Oleic Acid; Rabbits; Research

Topics: Animals; Arteriosclerosis; Atherosclerosis; Blood Chemical Analysis; Body Weight; Cholesterol; Dietary Proteins; Fatty Acids; Fatty Acids, Essential; Heparin; Hexosamines; Hypertension; Hypertension, Renal; Lanolin; Linoleic Acid; Lipoproteins; Pathology; Phospholipids; Rabbits; Research; Urea

Topics: Arteriosclerosis; Atherosclerosis; Dietary Fats; Glycerides; Heparin; Heparinoids; Hypercholesterolemia; Hyperlipidemias; Linoleic Acid; Lipid Metabolism; Lipoprotein Lipase; Niacin

Topics: Arteriosclerosis; Atherosclerosis; Blood Proteins; Cholesterol; Diet; Fatty Acids; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Lipids; Nutrition Assessment

Topics: alpha-Linolenic Acid; Arachidonic Acid; Arteriosclerosis; Atherosclerosis; Humans; Linoleic Acid; Lipoproteins

Topics: Acetates; Animals; Arteriosclerosis; Atherosclerosis; Chickens; Cholesterol; Linoleic Acid; Pyridoxine; Vitamin B 6