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.
Since the first observation of a marked triglyceride-lowering effect with salmon feeding in patients with severe hypertriglyceridemia, marine omega-3 fatty acids have been utilized clinically as a therapy for dyslipidemia.1 In a comprehensive review of human studies conducted to date, Harris2 reported reductions of 25% to 30% in serum triglycerides (TGs) with marine omega-3 fatty acids at intakes of 4 g/day, which were associated with modest increases of 5% to 10% in low-density lipoprotein (LDL) cholesterol and neutral effects on high-density lipoprotein (HDL) cholesterol (+1% to 3%). Despite demonstration of a dose-response relationship between omega-3 fatty acids and TG lowering, even low intakes of omega-3 fatty acids have been found to promote significant reductions in TGs,3 and 4 and postprandial hypertriglyceridemia is especially sensitive to long-term fish oil consumption.5 The mechanisms with which TG-lowering therapies such as fibrates or niacin exert their effects are fairly well established; however, a mechanism to explain the hypotriglyceridemic effects of omega-3 fatty acids has not been clarified. This article reviews the current understanding of TG metabolism to provide insight into potential mechanisms by which marine omega-3 fatty acids may reduce serum TG levels.
Regulation of Triglyceride Synthesis
TGs are synthesized in the hepatocyte in response to fluxes of glucose and nonesterified fatty acids (Figure 1).6 and 7 De novo TG synthesis is regulated by sterol regulatory element binding protein (SREBP)–1c, a hepatic gene transcription factor that stimulates synthesis of the lipogenic enzymes involved in this pathway (Figure 2).7 Glucose stimulates SREBP-1c indirectly either by providing TG substrates such as citrate or by increasing the release of insulin. Citrate is derived from glucose through conversion to pyruvate in a reaction mediated by pyruvate kinase, an enzyme that is not regulated by SREBP-1c.8 Pyruvate is then converted to citrate via the Krebs cycle, ultimately generating acetyl coenzyme A, the primary substrate for fatty acid synthesis. In addition, glucose-stimulated insulin release induces SREBP-1c gene transcription, which elevates levels of SREBP-1c that promote de novo lipogenesis. Glucose also increases lipogenesis by inhibiting the release of glucagon from the pancreas. Together these effects may explain the mechanisms by which a diet rich in simple carbohydrates, which rapidly increase serum glucose levels, can stimulate lipogenesis in both the liver and adipose tissue.8 Once synthesized, TGs are packaged with apolipoprotein B in a process mediated by microsomal transfer protein and secreted as very-low-density lipoprotein (VLDL)