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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 ≥4 metabolic nuclear receptors. These include liver X receptor, hepatocyte nuclear factor–4α (HNF-4α), 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-4α. 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.
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