ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid (PL) and free cholesterol (FC) from cells, forming nascent high density lipoproteins (nHDL). Because ABCA1 is variably expressed in most cells, we generated hepatocyte-specific ABCA1 KO (HSKO) mice to study the role of hepatocyte ABCA1 in lipid mobilization, transport, and metabolism. We found that hepatocyte ABCA1 regulates the production and catabolism of VLDL, LDL, and HDL, making hepatocyte ABCA1 a key modulator of lipid transport in all three major plasma lipoprotein classes that affect coronary heart disease (CHD) development. In preliminary studies, we found that hepatocyte ABCA1 also regulates hepatic insulin and inflammatory signaling, suggesting the function of hepatocyte ABCA1, while not fully elucidated, is more complex than facilitating bulk cellular cholesterol export and nHDL formation. The goal of this renewal is to determine the role of hepatocyte ABCA1 in liid mobilization and transport in HSKO mice and humans.
In specific aim 1, we will examine the role of hepatocyte ABCA1 expression in hepatic insulin signaling, inflammation, and lipogenesis. Metabolic phenotype, plasma VLDL metabolism, hepatic lipid synthesis, hepatic insulin receptor signaling, and hepatic plasma membrane lipid composition will be determined in chow and high fat-fed WT and HSKO mice.
In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We will investigate the plasma decay, hepatic uptake, re-secretion into plasma, and biliary and fecal excretion of HDL FC and CE, relative to apoA-I, in HSKO vs. WT mice.
In specific aim 3, the extent to which dietary polyunsaturated (poly) fat, relative to saturated (sat) and monounsaturated (mono) fat, reduces ABCA1 expression in human liver, intestine and adipose tissue will be explored. Interrelationships among tissue ABCA1 RNA and protein expression, plasma HDL cholesterol concentration, particle number and size, and plasma HDL FC efflux capacity as a function of dietary fat saturation will be determined.
In specific aim 4, we will determine whether rare coding ABCA1 sequence variants unique to African Americans (AA) (absent in European Americans, EA) affect lipid efflux as well as plasma HDL cholesterol concentration, particle number and size, and plasma HDL efflux potential. Associations between these measurements and coronary artery calcified plaque score, a measure of CHD, will be examined.
Coronary heart disease (CHD) remains the number one killer of US citizens. Liver (hepatocyte) ABCA1 expression affects the metabolism of al three major plasma lipoprotein classes (e.g., VLDL, LDL, HDL) that contribute to CHD risk and also affects hepatic insulin signaling. Studies outlined in this project will increase our fundamental knowledge of the causes of CHD and may help lead to improved strategies for prevention.
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