8-11-14-eicosatrienoic-acid and Hyperlipidemias

The study aims to investigate the effect of cytochrome P450 2J2 (CYP2J2) overexpression on hyperlipidemia in mice and further to explore its effect on fatty acid oxidation in vivo and in vitro.. The effects and mechanisms of endothelial-specific CYP2J2 transgene (Tie2-CYP2J2-Tr) on lipid and fatty acid metabolism were investigated in high-fat diet (HFD) -treated mice. HepG2, LO2 cells, and HUVECs were exposed to 0.4 mM free fatty acid (FFA) for 24 h and used as a model to investigate the roles of CYP2J2 overexpression and epoxyeicosatrienoic acids (EETs) on fatty acid β-oxidation in vitro.. Tie2-CYP2J2-Tr mice had significantly lower plasma and liver triglycerides, lower liver cholesterol and fatty acids, and reduced HFD-induced lipid accumulation. CYP2J2 overexpression resulted in activation of the hepatic and endothelial AMPKα, increased ACC phosphorylation, and increased expression of CPT-1 and PPARα, which were all reduced by HFD treatment. In FFA-treated HepG2, LO2, and HUVECs, both CYP2J2 overexpression and EETs significantly decreased lipid accumulation and increased fatty acid oxidation via activating the AMPK and PPARα pathways.. Endothelial-specific CYP2J2 overexpression alleviates HFD-induced hyperlipidemia in vivo. CYP2J2 ameliorates FFA-induced dyslipidemia via increased fatty acid oxidation mediated by the AMPK and PPARα pathways.

Topics: 8,11,14-Eicosatrienoic Acid; AMP-Activated Protein Kinases; Animals; Cholesterol; Diet, High-Fat; Disease Models, Animal; Fatty Acids; Fatty Acids, Nonesterified; Hyperlipidemias; Lipid Metabolism; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oxidative Stress; Triglycerides

We used liquid chromatography for analysis of fatty acids (FA) in lipids of erythrocytes of patients with hypertensive disease (HD) with normo- (group 1) and hyperlipidemia (group 2). Abnormalities of FA composition of erythrocyte lipids were revealed in both groups. In group 1 we found deficit of polyenic acids of omega-6 family, accumulation of Mead acid - prostanoid precursor with pronounced vasoconstrictor and pro inflammatory properties. In group 2 we noted more profound rearrangement of lipid matrix of erythrocyte membrane manifested as deficiency of omega-3 polyenic acids, accumulation of palmitinic and arachidonic acids. Preponderance of saturated FA in erythrocytes and deficiency of polyenic acids might evidence for pathology of their ligand-receptor transport into the cell. Blockade of active FA transport initiates formation of HD, promotes accumulation of atherogenic fractions of lipoproteins in blood. These results evidence for important pathogenetic role of FA in development of hypertension.

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acid; Atherosclerosis; Biological Transport, Active; Carbon-Carbon Double Bond Isomerases; Chromatography, Gas; Erythrocyte Membrane; Female; Humans; Hyperlipidemias; Hypertension; Inflammation Mediators; Lipoproteins; Male; Middle Aged; Palmitic Acid; Vasoconstriction

The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.

Topics: 8,11,14-Eicosatrienoic Acid; Amino Acids; Animals; Clofibrate; Cytochrome P-450 CYP4A; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epoxide Hydrolases; Epoxy Compounds; Hydroxyeicosatetraenoic Acids; Hyperglycemia; Hyperlipidemias; Kidney; Kidney Glomerulus; Male; Polymerase Chain Reaction; Protein Isoforms; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Circulation; Streptozocin; Transforming Growth Factor beta1

Lipid-lowering fibrate drugs are known to affect the synthesis of fatty acids, which may alter the prostacyclin synthesis in diabetic patients. Therefore, the serum levels of precursor fatty acids and 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) were determined in ten hyperlipidemic patients with Type 2 diabetes before and after administration of gemfibrozil (900 mg/day) for 3 months, in comparison with the results in seven non-diabetic hyperlipidemic patients. Gemfibrozil significantly reduced the serum concentration of dihomo-7-linolenic acid, total cholesterol and triglycerides, but did not affect the serum levels of arachidonic acid and 6-keto PGF1alpha in diabetic and non-diabetic patients. Thus, gemfibrozil did not affect the synthesis of prostacyclin in spite of the reduction of precursor fatty acids in diabetic and non-diabetic patients.

Topics: 6-Ketoprostaglandin F1 alpha; 8,11,14-Eicosatrienoic Acid; Aged; Arachidonic Acid; Cholesterol; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Triglycerides