8-11-14-eicosatrienoic-acid and Body-Weight

Zinc is an essential micronutrient for humans with important physiological functions. A sensitive and specific biomarker for assessing Zn status is still needed.. The major aim of this study was to examine if the changes in the content of plasma phospholipid LA, DGLA and LA: DGLA ratio can be used to efficiently predict the dietary Zn intake and plasma Zn status of humans.. The study was performed on healthy human volunteers, 25-55 years of age. The dietary Zn intake was assessed using 24 h recall questionnaires. Plasma phospholipid fatty acid analysis was done by gas chromatography, and plasma analysis of minerals by atomic absorption spectrometry. Biochemical, anthropometrical and hematological parameters were assessed.. No significant relationship was found between the dietary and plasma zinc status (r = 0.07; p = 0.6). There was a statistically significant correlation between DGLA and plasma Zn (r = 0.39, p = 0.00). No relationship was observed between the linoleic acid and plasma Zn, while there was a significant negative correlation between LA: DGLA ratio and plasma Zn status (r = -0.35, p = 0.01). Similarly, there were statistically significant difference in DGLA status (p = 0.004) and LA: DGLA ratio (p = 0.042) between the Zn formed groups.. This study is an initial step in evaluating LA: DGLA ratio as a biomarker of Zn status in humans. The results are encouraging as they show that concentration of DGLA is decreased and LA: DGLA ratio increased in people with lower dietary Zn intake. However, additional studies are needed to fully examine the sensitivity of this biomarker.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Biomarkers; Body Mass Index; Body Weight; Diet; Energy Intake; Fatty Acids; Female; Humans; Linoleic Acid; Male; Middle Aged; Nutritional Status; Phospholipids; Zinc

Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.

Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Diet, High-Fat; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Desaturases; Gene Expression; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice, Inbred C57BL; Obesity; Pyrimidinones; Pyrrolidinones; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss

Zinc is a vital micronutrient used for over 300 enzymatic reactions and multiple biochemical and structural processes in the body. To date, sensitive and specific biological markers of zinc status are still needed. The aim of this study was to evaluate Gallus gallus as an in vivo model in the context of assessing the sensitivity of a previously unexplored potential zinc biomarker, the erythrocyte linoleic acid: dihomo-γ-linolenic acid (LA:DGLA) ratio. Diets identical in composition were formulated and two groups of birds (n = 12) were randomly separated upon hatching into two diets, Zn⁺ (zinc adequate control, 42.3 μg/g zinc), and Zn⁻ (zinc deficient, 2.5 μg/g zinc). Dietary zinc intake, body weight, serum zinc, and the erythrocyte fatty acid profile were measured weekly. At the conclusion of the study, tissues were collected for gene expression analysis. Body weight, feed consumption, zinc intake, and serum zinc were higher in the Zn⁺ control versus Zn⁻ group (p < 0.05). Hepatic TNF-α, IL-1β, and IL-6 gene expression were higher in the Zn⁺ control group (p < 0.05), and hepatic Δ⁶ desaturase was significantly higher in the Zn⁺ group (p < 0.001). The LA:DGLA ratio was significantly elevated in the Zn⁻ group compared to the Zn⁺ group (22.6 ± 0.5 and 18.5 ± 0.5, % w/w, respectively, p < 0.001). This study suggests erythrocyte LA:DGLA is able to differentiate zinc status between zinc adequate and zinc deficient birds, and may be a sensitive biomarker to assess dietary zinc manipulation.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Biomarkers; Body Weight; Chickens; Diet; Erythrocytes; Fatty Acids; Gene Expression; Interleukin-1beta; Interleukin-6; Linoleic Acid; Liver; Nutritional Status; Phytic Acid; RNA, Ribosomal, 18S; Tumor Necrosis Factor-alpha; Zinc

Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Blood Pressure; Body Weight; Cardiotoxins; Chromatography, High Pressure Liquid; Doxorubicin; Epoxide Hydrolases; Genetic Predisposition to Disease; Heart Diseases; Kidney; Leukotriene D4; Male; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Troponin T; Ventricular Function, Left

Cats have limited Δ6 desaturase activity. However, γ-linolenate (GLA) feeding may by-pass the Δ6 desaturase step allowing arachidonate (ARA) accumulation via Δ5-desaturation. Alternatively, high dietary linoleate (LNA) may induce limited Δ6 desaturase also resulting in ARA accumulation. Fatty acid profiles were determined after feeding high LNA, high GLA, or adequate LNA diets. Adult female cats (n = 29) were assigned to one of three groups and fed for 8 weeks. Plasma samples were collected at weeks 0, 2, 4 and 8 for plasma triacylglycerol (TAG), total cholesterol (TC), lipoprotein (LP), and plasma and red blood cell membrane phospholipid fatty acid determinations. Time, but no diet, effects were observed for TAG, TC, and LP fractions at weeks 2 and 4 with significant increases likely due to increased dietary fat. However, all values were within feline normal limits. The GLA diet resulted in increased dihomo-γ-linolenic acid (DGLA) and ARA as early as week 2, supporting a ∆5 desaturase. Further evidence of Δ5 desaturase was found at high dietary LNA with the appearance of a novel fatty acid, 20:3 ∆7, 11, 14, apparently formed via ∆5 desaturation and chain elongation of LNA. However, Δ6 desaturase induction at high dietary LNA concentration was not observed. Cats are able to maintain plasma and red blood cell ARA when fed a practical diet containing GLA using what appears to be an active Δ5 desaturase enzyme.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Body Weight; Cats; Dietary Fats, Unsaturated; Fatty Acid Desaturases; Female; gamma-Linolenic Acid; Gas Chromatography-Mass Spectrometry; Linoleic Acid; Lipid Metabolism; Liver

Dihomo-gamma-linolenic acid (DGLA) is one of the essential fatty acids, and has anti-inflammatory and anti-allergic effects. To assess the toxicity of a novel DGLA oil produced by the fungus Mortierella alpina, we examined it in the Ames test and in acute and subchronic oral toxicity tests in rats. In the Ames test, no mutagenicity was found up to 5000 microg/plate. The acute toxicity test revealed no toxicity related to DGLA oil at 10 g/kg. In the subchronic toxicity test, DGLA oil (500, 1000, and 2000 mg/kg) was orally administered. Water and soybean oil (2000 mg/kg) were used for the no-oil control and soybean oil control groups, respectively. There was no death in either sex. Because of administration of large amounts of oil, food consumption was low in the soybean oil control and the three test groups, which appeared to mildly decrease urinary excretion of Na, K, and Cl, as well as total serum protein, albumin, and blood urea nitrogen levels. There were no toxicological changes in body weight, food consumption, ophthalmological examination, urinalysis, hematological examination, blood biochemical examination, necropsy, organ weight, or histopathological examination. These findings show that the no-observed-adverse-effect level of the DGLA oil was 2000 mg/kg.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blood Cell Count; Blood Chemical Analysis; Body Weight; Eating; Eye Diseases; Female; Male; Mortierella; Mutagenicity Tests; Organ Size; Rats; Rats, Sprague-Dawley; Urinalysis

1 This study examined the contribution of cytochrome P450 metabolites of arachidonic acid in mediating ischaemia/reperfusion (I/R)-induced cardiac dysfunction in normal and diabetic rats. 2 We first compared the metabolism of arachidonic acid in microsomes prepared from the hearts of control rats and rats treated with streptozotocin (55 mg kg(-1)) to induce diabetes. The production of dihydroxyeicosatrienoic acids and epoxyeicosatrienoic acids (EETs) were similar in microsomes prepared from the hearts of control and diabetic rats, but the production of 20-hydroxyeicosatetraenoic acid (20-HETE) was two-fold higher in diabetic hearts than in control animals. 3 We then compared the change in left ventricular pressure (P(max)), left ventricular end-diastolic pressure, coronary flow and coronary vascular resistance in isolated perfused hearts obtained from control and diabetic animals after 40 min of global ischaemia (I) followed by 30 min of reperfusion (R). The decline in cardiac function was three- to five-fold greater in the hearts obtained from diabetic vs. control animals. 4 Pretreatment of the hearts with N-hydroxy-N'-(4-butyl-2-methyl-phenyl)-formamidine (HET0016, 1 microm), a selective inhibitor of the synthesis of 20-HETE, for 30 min before I/R resulted in significant improvement in the recovery of cardiac function in the hearts obtained from diabetic but not in control rats. Perfusion with an inhibitor of soluble epoxide hydrolase, 1-cyclohexyl-3-dodecyl urea (CDU), before I/R improved the recovery of cardiac function in hearts obtained from both control and diabetic animals. Perfusion with both HET0016 and CDU resulted in significantly better recovery of cardiac function of diabetic hearts following I/R than that seen using either drug alone. Pretreatment of the hearts with glibenclamide (1 microm), an inhibitor of ATP-sensitive potassium channels, attenuated the cardioprotective effects of both CDU and HET0016. 5 This is the first study to suggest that acute blockade of the formation of 20-HETE and/or reduced inactivation of EETs could be an important strategy to reduce cardiac dysfunction following I/R events in diabetes.

Topics: 8,11,14-Eicosatrienoic Acid; Amidines; Animals; Arachidonic Acid; Blood Glucose; Body Weight; Coronary Circulation; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Epoxide Hydrolases; Glyburide; Heart; Hydroxyeicosatetraenoic Acids; Male; Microsomes; Myocardium; Rats; Rats, Wistar; Reperfusion Injury; Urea; Vascular Resistance; Ventricular Dysfunction, Left

Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-alpha and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-alpha and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesity-induced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.

Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Aorta; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Chemokine CCL2; Cytochrome P-450 Enzyme System; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Kidney Cortex; Membrane Proteins; Metabolic Syndrome; Mice; Mice, Knockout; Phenotype; Superoxides; Tumor Necrosis Factor-alpha; Vasodilation

Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA(2) expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA(2) enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA(2) in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion.

Topics: 8,11,14-Eicosatrienoic Acid; Acetylcholine; Animals; Arachidonic Acid; Bile Ducts; Blotting, Western; Body Weight; Cell Division; Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Hemodynamics; Kidney; Liver Cirrhosis; Nitric Oxide; Perfusion; Phospholipases A; Protein Isoforms; Rats; Time Factors

The dietary effect of 1,3-biseicosapentaenoyl-2-gamma-linolenoyl glycerol (STG) on the fatty acid composition of guinea pigs was examined and compared with that of an eicosapentaenoic acid ethyl ester (EPA-E) and of a soybean oil (SBO) diet. In terms of content of plasma lipid, EPA-E had a greater hypolipidemic effect than STG. On the other hand, in terms of EPA incorporation, contents of EPA in liver lipid were almost the same in the STG and EPA-E groups. Considering that the amount of EPA administered in the EPA-E group was almost 1.5 times that of the STG group, EPA may be absorbed more effectively as the glycerol ester than as the ethyl ester in guinea pigs. In all the tissue lipids, the STG group had a higher unsaturation index (UI) than the EPA-E group even though there is a lower UI in the STG diet than the EPA-E diet. These results suggest that greater amounts of desaturase products as a whole were synthesized in the STG group than in the other two groups. The dihomo-gamma-linolenic acid/arachidonic acid (DGLA/AA) ratio in plasma total lipids in the STG group was 3.5 times that of SBO group, and the DGLA/AA ratio in the EPA-E group was half that of the SBO group. In liver lipid, the ratios of DGLA/AA and EPA/AA in the STG group were 0.687 and 0.488 (phosphatidylcholine fraction) and 0.237 and 0.752 (phosphatidylethanolamine fraction), respectively. The ratio of DGLA/AA as well as the high EPA/AA ratio obtained in the present study with the STG diet may lead to physiological alterations, including enhanced synthesis of 1- and 3-series eicosanoids.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Blood Pressure; Body Weight; Cholesterol; Diet; Eicosapentaenoic Acid; Fatty Acid Desaturases; Fatty Acids; Guinea Pigs; Lipid Metabolism; Lipids; Liver; Male; Phospholipids; Soybean Oil; Triglycerides

Interest in the modulation of renal diseases by polyunsaturated fatty acids (PUFA) led this group to examine the effects of borage oil (BO) and corn oil (CO) in the rat 5/6-renal-ablation model. BO is a rich source of gamma-linolenic acid (GLA; 18:3n-6), which is elongated to dihomogamma-linolenic acid (DGLA; 20:3n-6). CO is a rich source of linoleic acid (LA; 18:2n-6), a GLA and arachidonic acid (AA; 20:4n-6) precursor. The purpose of this study was to assess whether an increased DGLA:AA ratio as provided by BO would confer benefits beyond those provided by LA present in corn oil. Forty rats were used for the experiment. Seven rats were used for presurgery measurements. The remaining animals were subjected to 5/6 nephrectomy. Surviving rats (N = 30) were fed regular laboratory diet (RLD) for 7 days, at which time seven rats were used to obtain 1-wk postnephrectomy data. The remainder were then allocated to receive either RLD (N = 8), 15% BO (N = 8), or 15% CO (N = 7) diets for 20 wk. Body weight, renal phospholipid levels, renal function (proteinuria and GFR), glomerular histology, glomerular macrophage infiltration, urinary prostaglandin levels (thromboxane B2 (TxB2), 6-keto-PGF1 alpha), plasma lipid levels, and blood pressure were measured. Diets were well tolerated by all groups with a similar age-related gain in weight throughout the study. Efficacy of the PUFA diets was confirmed by alteration in renal tissue phospholipids; LA decreased in the RLD and BO groups, but not in the CO group. AA was higher in the BO and CO rats, but only the BO group showed a rise in GLA and DGLA incorporation. Proteinuria increased progressively in the RLD group but remained at 1-wk postsurgery levels in the BO and CO groups. Decline in GFR and mesangial expansion were significantly lessened by BO supplementation only. Both PUFA diets limited glomerulosclerosis and macrophage infiltration, but direct comparisons between BO and CO groups revealed significantly less glomerulosclerosis and macrophage infiltration in the BO group. Both BO and CO attenuated the rise in the TxB2 excretion rate and restored the 6-keto-PGF1 alpha:TxB2 ratio to the 1-wk postsurgery level. Plasma lipid levels rose in all groups, but the rise in cholesterol level was less in the BO and CO rats, CO being the most efficacious in this regard. BP increased progressively in RLD rats, but not in the BO and CO groups, BO providing a markedly greater hypotensive effect. In summary, both CO and BO supplemen

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Body Weight; Corn Oil; Dietary Fats, Unsaturated; gamma-Linolenic Acid; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Kidney; Lipids; Macrophages; Male; Nephrectomy; Phospholipids; Plant Oils; Rats; Rats, Sprague-Dawley

Age-related changes in delta 6 desaturation of [1-14C]alpha-linolenic acid and [1-14C]linoleic acid and in delta 5 desaturation of [2-14C]dihomo-gamma-linolenic acid were studied in liver microsomes from Wistar male rats at various ages ranging from 1.5 to 24 mon. Desaturase activities were expressed both as specific activity of liver microsomes and as the capacity of whole liver to desaturate by taking into account the total amount of liver microsomal protein. delta 6 Desaturation of alpha-linolenic acid increased from 1.5 to 3 mon and then decreased linearly up to 24 mon to reach the same desaturation capacity of liver measured at 1.5 mon. The capacity of liver to desaturate linoleic acid increased up to 6 mon and then remained constant, whereas microsomal specific activity was equal at 1.5 and 24 mon of age. The capacity of liver to convert dihomo-gamma-linolenic acid to arachidonic acid by delta 5 desaturation decreased markedly from 1.5 to 3 mon. It then increased to reach, at 24 mon, the same level as that observed at 1.5 mon. Age-related changes in the fatty acid composition of liver microsomal phospholipids at the seven time points studied and of erythrocyte lipids at 1.5 and 24 mon were consistent with the variations in desaturation capacity of liver. In particular, arachidonic acid content in old rats was slightly higher than in young rats whereas contents in linoleic and docosahexaenoic acids varied little throughout the life span.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8,11,14-Eicosatrienoic Acid; Aging; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Fatty Acid Desaturases; Fatty Acids; Fatty Acids, Unsaturated; Linoleic Acid; Linoleic Acids; Linoleoyl-CoA Desaturase; Liver; Male; Microsomes, Liver; Organ Size; Phospholipids; Rats

We studied linoleic acid delta 5 and dihomo-gamma-linolenic acid delta 5 desaturations, and fatty acid composition, of liver microsomes in the insulin-dependent spontaneously diabetic adult female BB rat. These desaturations were defective along the normo- and hyper-glycemic period and restored during the hypoglycemic period which followed the insulin injection to the diabetic rats. The fatty acid composition of BB rats microsomes was not consistent with the desaturase activities at the different periods of glycemia, probably because other factors than desaturation impairments were involved in the evolution of fatty acid composition.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blood Glucose; Body Weight; Delta-5 Fatty Acid Desaturase; Diabetes Mellitus, Experimental; Fatty Acid Desaturases; Female; Insulin; Linoleic Acid; Linoleic Acids; Linoleoyl-CoA Desaturase; Microsomes, Liver; Organ Size; Rats; Rats, Inbred BB; Rats, Inbred Strains