Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids.
A mechanism to explain the hypotriglyceridemic effects of marine omega-3 fatty acids in humans has not been clarified. A working model can be developed at the gene transcriptional level, which involves >or=4 metabolic nuclear receptors. These include liver X receptor, hepatocyte nuclear factor-4alpha (HNF-4alpha), farnesol X receptor, and peroxisome proliferator-activated receptors (PPARs). Each of these receptors is regulated by sterol receptor element binding protein-1c (SREBP-1c), the main genetic switch controlling lipogenesis. Omega-3 fatty acids elicit hypotriglyceridemic effects by coordinately suppressing hepatic lipogenesis through reducing levels of SREBP-1c, upregulating fatty oxidation in the liver and skeletal muscle through PPAR activation, and enhancing flux of glucose to glycogen through downregulation of HNF-4alpha. The net result is the repartitioning of metabolic fuel from triglyceride storage toward oxidation, thereby reducing the substrate available for very-low-density lipoprotein (VLDL) synthesis. By simultaneously downregulating genes encoding proteins that stimulate lipid synthesis and upregulating genes encoding proteins that stimulate fatty acid oxidation, omega-3 fatty acids are more potent hypotriglyceridemic agents than are omega-6 fatty acids, on a carbon-for-carbon basis. Additionally, peroxidation of omega-3 fatty acids may reduce VLDL secretion through stimulating apolipoprotein B degradation. Omega-3 fatty acids may act by enhancing postprandial chylomicron clearance through reduced VLDL secretion and by directly stimulating lipoprotein lipase activity. These combined effects support the use of omega-3 fatty acids as a valuable clinical tool for the treatment of hypertriglyceridemia.
Davidson
Michael H
MH
Radiant Research and Rush University Medical Center, Chicago, Illinois, USA. michaeldavidson@radiantresearch.com
D000818:Animals; D001711:Biotransformation / Q000235:genetics; D015536:Down-Regulation; D050171:Dyslipidemias / Q000378:metabolism* / Q000503:physiopathology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000096:biosynthesis; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D019518:Postprandial Period; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
D015525:Fatty Acids, Omega-3; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D008079:Lipoproteins, VLDL; D047492:Peroxisome Proliferator-Activated Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides