Insulin regulated hepatic apo B lipoprotein biogenesis

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EXCEED THE SPACE PROVIDED. Control of hepatic apo B secretion by insulin may serve a regulatory role in balancing intestinal vs. hepatic triglyceride-rich lipoprotein (TRL) metabolism. In insulin resistant states including diabetes and obesity hypertriglyceridemia is a factor in accelerated atherogenesis resulting in heart attacks, strokes, and peripheral vascular disease. Insulin suppresses hepatic apo B through decreased synthesis and increased intracellular degradation, and the pathway is mediated by the insulin receptor. Specific resistance of insulin receptor mediated inhibition of apo B, which may occur in obesity and diabetes, would result in increased numbers of secreted TRL and aggravate post-prandial hypertriglyceridemia. Proposed studies place the pathway into pathophysiologic context. Targeting of activated phosphoinositide 3-kinase (PI 3-K) to the endoplasmic reticulum (ER) and generation of charged product phospholipids (PIP-3) are proposed to interfere with apo B synthesis and secretion and result in apo B degradation. Aim 1 is to define the physiologic relevance of insulin to inhibit the secretion of hepatic apo B in rats (B48/B100 model), in hamsters (B100 model), and in genetically altered mice (B100 model) and establish that short term hyperinsulinemia results in longer term suppression of hepatic apo B, minimizing competition between hepatic and intestinal lipoprotein particles. Loss of the suppressive effect of insulin on apo B occurs with insulin resistance which results in inappropriate apo B synthesis and secretion and prolonged post-prandial hypertriglyceridemia Apo B metabolism in insulin resistant animal models including the Zucker Diabetic Fatty rat and fructose fed hamster will be characterized. Aim 2 is to determine signaling events mediated by PI 3-K resultant from translocation of activated PI 3-K into the ER and to determine the mechanism of resistance in this pathway in suppression of hepatic apo B secretion in insulin resistant models.The hypothesis is that defective localization of PI 3-K activity to specific ER compartments may be involved in insulin resistance. Specific insulin dependent PI 3-K pathways may be involved in hepatic apo B biogenesis and the proposed studies will provide new insight into specialized pathways mediated by insulin which are involved in the hypertriglyceridemia of insulin resistance syndromes. PERFORMANCE SITE ========================================Section End===========================================