Increased secretion of apoliprotein B (apoB)-lipoproteins (Lps) characterizes both animal models and humans with dyslipidemia accompanying IR and type 2 diabetes mellitus (T2DM). The goal of the proposed studies is to provide new and unique insights into the integrated roles that hepatic fatty acids (FA) and triglycerides (TG), plasma FA, and hepatic insulin signaling play in determining both the secretion of apoB- Lps and development of hepatic steatosis. Of particular interest is the question: Why does hepatic steatosis occurs despite increased secretion of apoB-Lps in animals and people with IR. Our first hypothesis focuses on the roles of hepatic FA and TG on the assembly and secretion of apoB-Lps. The 3 aims under Hypothesis 1, test our belief that increased hepatic TG, from any source, is a potent determinant of the quantity of TG added to each apoB-Lp, but has only a minimal to modest effect on the number of particles secreted. We believe that the inability of increased hepatic TG to adequately stimulate secretion of increased numbers of apoB-Lps predisposes to steatosis. By contrast, we propose that increased uptake of circulating FA by the liver potently stimulates the secretion of increased numbers of apoB-Lps, potentially protecting against steatosis while possibly worsening the dyslipidemia. Importantly, we believe that FA- mediated stimulation of apoB-Lp secretion is independent of its incorporation into a common TG pool, and that FA from hepatic DNS do not effectively stimulate apoB-Lp secretion. The second hypothesis focuses on insulin-mediated degradation of apoB. The 4 aims under Hypothesis 2 focus on whether the effects of hepatic insulin signaling on apoB-Lp secretion will be modulated by hepatic TG and by FA from the circulation. We believe that increased hepatic TG will reduce insulin-mediated post-ER degradation of apoB while increased hepatic uptake of FA will reduce both insulin-mediated ER and post-ER degradation of apoB. Reduced hepatic insulin signaling will cause more apoB secretion and less hepatic TG, irrespective of prevailing hepatic synthesis of TG or FA flux. Finally, Hypothesis 3 and the aims that follow will focus on the possibility that ER stress, mediated by high fat diets or insulin resistance, alters apoB secretion. If ER stress partially inhibits apoB-Lp secretion that would predispose to steatosis. All of these studies will lead to a clearer understanding of, and new approaches to the treatment of dyslipidemia and hepatic steatosis.
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