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 Presentation

"Metabolic Complications of Insulin Resistance: Focus on lipid abnormalities"

Dr. Gary F. Lewis (biography)
English - 2002-04-26 - 43 minutes
(39 slides)

Summary :
Hyperlipidemia is a common consequence of the insulin-resistant state, and is felt to contribute significantly to the increased propensity to develop premature and aggressive atherosclerosis. The most common lipid abnormalities of diabetes and other insulin-resistant states are hypertriglyceridemia and reduction in the cholesterol content, and numbers of high density lipoprotein (HDL) particles. Our interest has been in elucidating the mechanisms whereby the production of very low-density lipoprotein (VLDL) particles, the major carrier of endogenously-synthesized triglycerides, is increased in insulin-resistant states, and the mechanism of the reduction in plasma levels of HDL particles. We have used predominantly in vivo methods in the whole body, research that can be termed "integrative physiology/biology". In collaboration with other researchers, we have also been able to examine these processes at the cell and molecular level.

<b>Mechanisms whereby the production of VLDL particles is increased.</b>
Insulin plays a pivotal role in controlling the supply of VLDL biosynthethic precursors to the liver (particularly free fatty acids (FFA), by its action in extrahepatic tissues and also affects multiple steps in the hepatocyte VLDL biosynthetic pathway in a direct or indirect fashion. Data from in vitro and cultured hepatocyte studies will be presented to indicate that insulin-resistant states are associated with a combination of events that lead to high rates of hepatic VLDL secretion. These include, but are not limited to, elevated FFA flux to the liver, elevated hepatic de novo lipogenesis and triglyceride esterification, resistance to insulin's acute inhibitory effect on apolipoprotein B stability, enhanced lipoprotein assembly, and secretion.

<b>Mechanisms whereby HDL cholesterol content and particle numbers are reduced.</b>
Hypertriglyceridemia, a common feature of insulin-resistant states, is commonly associated with triglyceride (TG)-enrichment of HDL and reduction in HDL cholesterol and apo A1 (the major protein moiety of HDL levels). In vivo studies will be presented, demonstrating the importance of HDL TG enrichment, coupled with lipolysis by hepatic lipase, in enhancing HDL clearance from the circulation. TG-enrichment of HDL, in the absence of substantial lipolytic modification, is not sufficient to enhance its clearance from the circulation. This phenomenon could provide an important mechanism explaining how HDL apo A1 and HDL-c are lowered in hypertriglyceridemic states, thereby leading to accelerated atherosclerosis.

Learning objectives :
Drawing largely on the research carried out in his own lab, Dr Lewis discusses the following:
1.Some mechanisms of HDL lowering in insulin resistant and type 2 diabetic conditions.
2.Mechanisms of overproduction of very low density lipoproteins (VLDLs) leading to hypertriglyceridemia.
3.Recent and unpublished work looking at intestinal lipoprotein overproduction in insulin resistant states.



Bibliographic references :
Fasting and Postprandial Overproduction of Intestinally Derived Lipoproteins in an Animal Model of Insulin Resistance. EVIDENCE THAT CHRONIC FRUCTOSE FEEDING IN THE HAMSTER IS ACCOMPANIED BY ENHANCED INTESTINAL DE NOVO LIPOGENESIS AND ApoB48-CONTAINING LIPOPROTEIN OVERPRODUCTION.

Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, Adeli K.

Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children and the Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.

J Biol Chem 2002 Aug 30;277(35):31646-55

   


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