Liver ABCA1, Lipoprotein Metabolism and Atherosclerosis

ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid and free cholesterol from cells, forming nascent high density lipoproteins (HDLs). 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.

Our previous studies showed that hepatocyte ABCA1 regulates the production and catabolism of all three major plasma lipoprotein classes (VLDL, LDL and HDL) that affect coronary heart disease 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 nascent HDL formation.

Our Goal

The goal of this project is to determine the role of hepatocyte ABCA1 in lipid mobilization and transport in HSKO mice and humans.

Specific Aim 1

In specific aim 1, we are examining 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 are being determined in chow and high fat-fed wild type and HSKO mice.

Specific Aim 2

In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We are investigating 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.

Specific Aim 3

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.

Specific Aim 4

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.