8-11-14-eicosatrienoic-acid and Fatty-Liver

Triacylglycerol accumulation in the liver (fatty liver) caused by ethanol or carbon tetrachloride involves interactions with essential fatty acids and prostaglandins. The degree to which the fatty liver develops is dependent on total dietary fat intake. Both ethanol and carbon tetrachloride impair desaturation of linoleic acid and dihomo-gamma-linolenic acid and this appears to be relevant to the pathogenesis of fatty liver from two points of view. First, low arachidonic acid in liver phospholipids is associated with increased liver triacylglycerol content whether caused by ethanol, carbon tetrachloride, or essential fatty acid deficiency. Second, essential fatty acids including gamma-linolenic acid and arachidonic acid, as well as the prostaglandins, prevent ethanol- and carbon tetrachloride-induced fatty liver. Arachidonic acid and possibly the prostaglandins are therefore likely to be directly involved in lipoprotein and triacylglycerol secretion by the liver.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Arachidonic Acids; Carbon Tetrachloride; Cricetinae; Dietary Fats; Ethanol; Fatty Acids, Essential; Fatty Liver; Fatty Liver, Alcoholic; gamma-Linolenic Acid; Guinea Pigs; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Liver; Mice; Prostaglandins; Rats; Species Specificity; Triglycerides

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and is considered to be an inflammatory disorder characterized by fatty acid accumulation, oxidative stress, and lipotoxicity. We have previously reported that epoxyeicosatrienoic acid-agonist (EET-A) has multiple beneficial effects on cardiac, renal and adipose tissue function while exhibiting both anti-inflammatory and anti-oxidant activities. We hypothesized that EET-A intervention would play a central role in attenuation of obesity-induced steatosis and hepatic fibrosis that leads to NAFLD.. We studied the effect of EET-A on fatty liver using db/db mice as a model of obesity. Mice were fed a high fat diet (HFD) for 16 weeks and administered EET-A twice weekly for the final 8 weeks.. db/db mice fed HFD significantly increased hepatic lipid accumulation as manifested by increases in NAS scores, hepatic fibrosis, insulin resistance, and inflammation, and decreases in mitochondrial mitofusin proteins (Mfn 1/2) and anti-obesity genes Fibroblast growth factor 21 (FGF21) and Cellular Repressor of E1A-Stimulated Genes 1 (CREG1). EET-A administration reversed the decrease in these genes and reduced liver fibrosis. Knockout of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in EET-A treated mice resulted in a reversal of the beneficial effects of EET-A administration.. EET-A intervention diminishes fatty acid accumulation, fibrosis, and NFALD associated with an increase in HO-1-PGC1α and increased insulin receptor phosphorylation. A pharmacological strategy involving EETs may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NAFLD.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Disease Models, Animal; Fatty Liver; Heme Oxygenase-1; Mice; Mitochondria; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Leptin; Signal Transduction

Fatty acid desaturase 2 (FADS2) is responsible for the first desaturation reaction in the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5n-3), and is involved in Mead acid (20:3n-9) production during essential fatty acid deficiency (EFAD). In this study, an obvious hepatic lipid accumulation was observed in EFAD mice treated with a FADS2 inhibitor. FADS2 inhibition in the EFAD state reduced secretion of very low-density lipoprotein (VLDL) and markedly diminished Mead acid in phosphatidylcholine (PC) in the liver and plasma. As the results, the amount of C20 HUFAs in hepatic and plasma PC dramatically reduced in the EFAD mice treated with a FADS2 inhibitor, whereas the decrease of C20 HUFA levels of PC in EFAD mice was not observed because of the increased Mead acid in PC. These results supposed that Mead acid in PC is important as a component of VLDL. It is possible that Mead acid plays the role of a substitute of HUFAs in VLDL secretion during EFAD.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Fatty Acid Desaturases; Fatty Acids, Unsaturated; Fatty Liver; Lipid Metabolism; Lipoproteins, VLDL; Liver; Male; Mice, Inbred C57BL; Oxidation-Reduction; Phosphatidylcholines

Cytokeratin (CK) 18 M30 antigen has been proposed as a diagnostic marker of nonalcoholic fatty liver disease (NAFLD). We studied serum CK18 M30 antigen level and examined the correlations among CK18 and biological data, dietary intake, and plasma fatty acid composition in middle-aged Japanese males with (NAFLD; n=42) and without NAFLD (control; n=35). NAFLD was diagnosed if subjects showed fatty liver on abdominal ultrasonography and their alcohol consumption was <20 g/d. They were also confirmed to have negative serological results for tests of autoimmune liver disease and hepatitis B and C. In the NAFLD group, body mass index, waist circumference, serum M30 antigen, alanine transaminase (ALT), cholinesterase, triacylglycerol, LDL-cholesterol, and HbA1c were significantly higher than in the control group. In the fatty acid analysis of plasma phospholipids, significantly higher dihomo-γ-linolenic acid (DGLA), total saturated fatty acids (SFA), and palmitic/linoleic acid ratio as well as lower arachidonic acid/DGLA ratio were observed in the NAFLD group compared with the control group. In the NAFLD group, M30 antigen was correlated positively with serum ALT, plasma DGLA, dietary SFA, and serum TNF-α as determined by partial correlation analysis controlled for BMI. On the basis of multivariate regression analysis using a stepwise method, M30 antigen was significantly associated with ALT and plasma DGLA. Regarding the determinants of NAFLD as revealed by logistic regression analysis, a high odds ratio was observed for plasma DGLA. In conclusion, members of the NAFLD group showed higher levels of serum CK18 M30 antigen and M30 antigen was strongly associated with serum ALT and plasma DGLA. Abnormal fatty acid metabolism may be a factor that causes aggravation of NAFLD.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Alanine Transaminase; Asian People; Body Mass Index; Diet; Eating; Fatty Acids; Fatty Liver; Humans; Japan; Keratin-18; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Regression Analysis; Tumor Necrosis Factor-alpha; Waist Circumference