MITOCHONDRION IS THE PRINCIPAL TARGET FOR NUTRITIONAL AND PHARMACOLOGICAL CONTROL OF TRIGLYCERIDE-METABOLISM

Fish oil polyunsaturated fatty acids and fibrate hypolipidemic drugs a re potent hypotriglyceridemic agents that act by increasing fatty acid catabolism and decreasing triglyceride synthesis and secretion by the liver. A major unresolved issue is whether this hypotriglyceridemic e ffect can occur independent of induction of peroxisomal beta-oxidation , a predisposing factor for hepatocarcinogenesis. The present study wa s undertaken to determine which component of fish oil, eicosapentaenoi c acid (FPA) or docosahexaenoic acid (DHA), is responsible for its tri glyceride-lowering effect. We demonstrate that EPA and not DKA is the hypotriglyceridemic component of fish oil and that mitochondria and no t peroxisomes are the principal target. Results obtained by fenofibrat e feeding support the hypothesis that the mitochondrion is the primary site for the hypotriglyceridemic effect. In contrast to fibrates, EPA did not affect hepatic apolipoprotein C-III gene expression. Therefor e, increased mitochondrial beta-oxidation with a concomitant decrease in triglyceride synthesis and secretion seems to be the primary mechan ism underlying the hypotriglyceridemic effect of EPA and fibrates in r ats, rabbits and possibly also in humans. In addition, these data show that lowering of plasma triglycerides can occur independently of any deleterious peroxisome proliferation.