ATP binding cassette transporter A1 (ABCA1) is a membrane protein that functions to assemble nascenthigh density lipoprotein (HDL) particles. ABCA1 is expressed in many cells but the cell-specific role of thetransporter in lipoprotein metabolism and the development of atherosclerosis are poorly understood. Duringthe last grant cycle, we developed a hepatocyte-specific ABCA1 knockout (HSKO) mouse that had lowplasma 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 mechanisticallyhow 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 hepatocyteABCA1 will result in a corresponding decrease in reverse cholesterol transport (RCT) and an increasein atherosclerosis in the context of hyperlipidemia.
In specific aim 2, we will determine the molecular pathwaysby which hepatocyte-specific deletion of ABCA1 reduces plasma apoB lipoprotein levels and elevatesplasma TG concentrations. We will investigate the following hypotheses: 1) that ABCA1 functions to increaseGolgi to plasma membrane vesicular trafficking, resulting in reduced efficiency of second step VLDL particleassembly, decreased TG secretion, and smaller VLDL particles, 2) that nascent HDL particles assembled byhepatic ABCA1 signal through a PIS kinase-mediated pathway to decrease VLDL TG secretion by decreasingsecond step VLDL particle assembly, and 3) that plasma turnover of apoB LPs is increased in HSKOmice 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 themolecular 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 nascentHDL particles by ABCA1 that will be preferentially catabolized by the liver rather than the kidney due to increasedlipid content, a change in apoA-l conformation, an increased ability to efflux lipid, and/or increasedLCAT 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 hepatocyteABCA1 in lipoprotein metabolism and atherosclerosis and will take advantage of a unique ABCA1 HSKOmouse model developed by the project. The proposed studies also will investigate gaps in knowledge relatedto the formation, remodeling, maturation, and catabolism of HDL particles, resulting in a better understandingof HDL metabolism and RCT as relates to the development of atherosclerosis.
Showing the most recent 10 out of 242 publications
