Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids

Am J Cardiol. 2006 Aug 21;98(4A):27i-33i. doi: 10.1016/j.amjcard.2005.12.024. Epub 2006 May 26.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Biotransformation / genetics
  • Down-Regulation
  • Dyslipidemias / metabolism*
  • Dyslipidemias / physiopathology
  • Fatty Acids, Omega-3 / metabolism*
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Humans
  • Lipid Peroxidation / genetics
  • Lipogenesis / genetics
  • Lipoproteins, VLDL / biosynthesis
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Postprandial Period
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / biosynthesis
  • Triglycerides / metabolism*


  • Fatty Acids, Omega-3
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Lipoproteins, VLDL
  • Peroxisome Proliferator-Activated Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides