An emerging trend suggests that apoB lipoprotein particle number, and not LDL cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease.
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.
Our Goal
We are exploring 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 being conducted.
Specific Aim 1
Aim 1 will define the physiologic and pathophysiologic settings that regulate apoA-IV expression in liver and will establish whether it is hepatic triglyceride (TG) accumulation that induces apoA-IV expression or whether the regulation of apoA-IV is linked to processes associated with enhanced assembly and secretion of VLDL.
Specific Aim 2
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, reducing hepatic lipid burden.
Specific Aim 3
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.About ABCA1
An emerging trend suggests that apoB lipoprotein particle number, and not LDL cholesterol, may best predict susceptibility to atherosclerotic cardiovascular disease.
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.