An emerging trend suggests that apoB lipoprotein particle number, and not LDL- cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease (CVD). As very low density lipoprotein (VLDL) particle size is heterogeneous, reflecting the elasticity of the apoB lipoprotein assembly process, an unanswered question with relevance to many aspects of the metabolic syndrome is how the hepatocyte integrates particle number with particle size to achieve a given rate of hepatic lipid efflux. An overall goal of the current proposal is to explore the hypothesis that apolipoprotein A-IV (apoA-IV) is acutely regulated and serves an important role in hepatic lipid efflux by promoting nascent VLDL particle expansion. Defining this previously unknown role of apoA- IV in hepatic lipid metabolism and understanding the mechanism by which it functions has important translational potential, as it is likely that if VLDL-mediated lipid efflux could be achieved by a process of particle expansion at the expense of particle number, a less atherogenic lipoprotein profile may result, while still protecting the liver from steatosis. To explore and validate this hypothesis, three specific aims are proposed.
Aim 1 will define the physiologic and pathophysiologic settings that regulate apoA-IV expressin in liver and will establish whether it is hepatic triglyceride (TG) acumulation that induces apoA-IV expression or whether the regulation of apoA-IV is linked to processes associated with enhanced assembly and secretion of VLDL.
Aim 2 will establish the impact of apoA-IV on TG secretion and hepatic lipid content and pathophysiology. These studies are supported by preliminary data demonstrating that overexpression of apoA-IV in mouse liver both dramatically induces TG secretion and also dramatically reduces hepatic lipid burden. Finally, Aim 3 will focus on the mechanism by which apoA-IV promotes TG secretion and will explore the hypothesis that a direct-apoA-IV-apoB interaction alters the trafficking kinetics of apoB and promotes greater incorporation of lipid into nascent VLDL particles, while reducing total VLDL particle production.
The epidemic of obesity and insulin resistance has caused a rapid increase in the incidence of nonalcoholic fatty liver disease. This proposal will explore the hypothesis that the induction of apoA-IV expression promotes hepatic lipid secretion by promoting VLDL particle expansion. We further propose that If VLDL-mediated lipid efflux could be achieved by a process of particle expansion at the expense of particle number a less atherogenic lipoprotein profile may ensue with while still protecting the liver from toxic lipid accumulation.
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