ATP binding cassette transporter A1 (ABCA1) is a membrane protein that functions to assemble nascent high density lipoprotein (HDL) particles. ABCA1 is expressed in many cells but the cell-specific role of the transporter in lipoprotein metabolism and the development of atherosclerosis are poorly understood. During the last grant cycle, we developed a hepatocyte-specific ABCA1 knockout (HSKO) mouse that had low plasma HDL (20% of normal) and LDL concentrations (50% of normal) and elevated triglyceride (TG) concentrations (2-fold) compared with wild type mice. The goal of our renewal is to understand mechanistically how hepatocyte-specific expression of ABCA1 impacts lipoprotein metabolism and the development of atherosclerosis.
In specific aim 1, we will test the hypothesis that a gene dosage dependent decrease in hepatocyte ABCA1 will result in a corresponding decrease in reverse cholesterol transport (RCT) and an increase in atherosclerosis in the context of hyperlipidemia.
In specific aim 2, we will determine the molecular pathways by which hepatocyte-specific deletion of ABCA1 reduces plasma apoB lipoprotein levels and elevates plasma TG concentrations. We will investigate the following hypotheses: 1) that ABCA1 functions to increase Golgi to plasma membrane vesicular trafficking, resulting in reduced efficiency of second step VLDL particle assembly, decreased TG secretion, and smaller VLDL particles, 2) that nascent HDL particles assembled by hepatic ABCA1 signal through a PIS kinase-mediated pathway to decrease VLDL TG secretion by decreasing second step VLDL particle assembly, and 3) that plasma turnover of apoB LPs is increased in HSKO mice due to enrichment in particle TG content, resulting in larger VLDL, and/or altered apolipoprotein content.
In specific aim 3, we will determine the impact of expression of a novel apolipoprotein, apoM, on the molecular steps of ABCA1-mediated nascent HDL particle assembly, intravascular remodeling/maturation, and in vivo catabolism. We hypothesize that apoM expression will result in the production of larger nascent HDL particles by ABCA1 that will be preferentially catabolized by the liver rather than the kidney due to increased lipid content, a change in apoA-l conformation, an increased ability to efflux lipid, and/or increased LCAT reactivity compare to nascent HDL particles assembled by ABCA1 in the absence of apoM expression. Results from these studies will increase our fundamental understanding of the role of hepatocyte ABCA1 in lipoprotein metabolism and atherosclerosis and will take advantage of a unique ABCA1 HSKO mouse model developed by the project. The proposed studies also will investigate gaps in knowledge related to the formation, remodeling, maturation, and catabolism of HDL particles, resulting in a better understanding of HDL metabolism and RCT as relates to the development of atherosclerosis.
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