Mechanisms of metabolic dyslipidemia in insulin resistant states: deregulation of hepatic and intestinal lipoprotein secretion.
The growing epidemic of the metabolic syndrome is now well recognized and there is widespread effort to understand the pathogenesis of this complex syndrome and its major metabolic consequences. One of the severe complications accompanying insulin resistant states is the hypertriglyceridemia that appears to occur largely due to overproduction of triglyceride-rich, apolipoprotein B (apoB) containing-lipoproteins. As a result, mechanisms regulating the overproduction of these atherogenic apoB-containing lipoproteins have been the focus of much investigation in recent years. Both in vitro as well as in vivo models of insulin resistance are currently being used to further our understanding of the mechanisms involved in the deregulation of lipid metabolism in insulin resistant states. Evidence from these animal models as well as human studies has identified hepatic very low density lipoprotein (VLDL) overproduction as a critical underlying factor in the development of hypertriglyceridemia and metabolic dyslipidemia. In recent years, a dietary animal model of insulin resistance, the fructose-fed hamster model developed in our laboratory, has proven invaluable in studies of the link between development of an insulin resistant state, derangement of hepatic lipoprotein metabolism, and overproduction of apoB-containing lipoproteins. Evidence from the fructose-fed hamster model now indicates oversecretion of both hepatically-derived apoB100-containing VLDL as well as intestinal apoB48-containing triglyceride-rich lipoproteins in insulin resistant states. A number of novel intracellular factors that may be involved in modulation of VLDL have also been identified. This review focuses on these recent developments and examines the hypothesis that a complex interaction among enhanced flux of free fatty acids from peripheral tissues to liver and intestine, chronic up-regulation of de novo lipogenesis by hyperinsulinemia, and attenuated insulin signaling in the liver and the intestine may be critical to lipoprotein overproduction accompanying insulin resistance.
Avramoglu
Rita Kohen
RK
Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Qiu
Wei
W
Adeli
Khosrow
K
D000818:Animals; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000378:metabolism*
D008074:Lipoproteins