The current model for reverse cholesterol transport proposes that HDL transports excess cholesterol derived primarily from peripheral cells to the liver for removal. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic contribution to plasma HDL-C levels, we generated an adenovirus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GFP in vivo to the liver. Compared with mice injected with control AdV, infusion of rABCA1-GFP-AdV into C57Bl/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepatocytes isolated 1 day after rABCA1-GFP-AdV infusion. Hepatic ABCA1 expression in C57Bl/6 mice (n ‫؍‬ 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150-300% ( P Ͻ 0.05 all). ABCA1 expression led to significant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reductase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver.These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing pathways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDL-C. The role of HDL in the removal of excess cholesterol from peripheral cells was postulated nearly 30 years ago and designated reverse cholesterol transport (RCT) (1, 2). In the current working model of RCT, excess cholesterol is removed from peripheral cells and esterified by lecithin cholesterol acyltransferase. The cholesteryl ester is then transported back to the liver for removal from the body, either directly by HDL or following transfer by cholesterol ester transfer protein to the apoB-containing lipoproteins. This model proposes that cholesterol and lipids used for the formation and maturation of HDL are derived from nonhepatic, peripheral cells as well as from the metabolism and remodeling of the triglyceride-rich, apoBcontaining lipoproteins. Previous reports indicate that the liver is an important source of apoA-I and thus contributes significantly to the plasma pool of nascent HDL (3, 4). However, although the liver is the most important modulator of cholesterol homeostasis in the body, it has not been implicated as a major in vivo source of cholesterol to lipidate HDL in the circulation .A major advance in our understanding of the first step in reverse cholesterol transport was the identification of the ABCA1 transporter as the genetic defect in patients with Tangier disease (5-10). ABCA1 is the major transporter that facilitates the efflux of cholesterol and phospholipids to poorly lipidated apoA-I to form nascent or pre ␤ HDL. In the absence of a functional ABCA1 transporter, patients with Tangier disease are unable to efflux cholesterol to apoA-I and accumulate cholesteryl esters in many tissues, including arterial macrophages. Attie et al. reported similar findings in the ...

Abstract-High-density lipoproteins (HDL) protect against cardiovascular disease. HDL removes and transports excess cholesterol from peripheral cells to the liver for removal from the body. HDL also protects low-density lipoproteins (LDL) from oxidation and inhibits expression of adhesion molecules in endothelial cells, preventing monocyte movement into the vessel wall. The ABCA1 transporter regulates intracellular cholesterol levels in the liver and in peripheral cells by effluxing excess cholesterol to lipid-poor apoA-I to form nascent HDL, which is converted to mature ␣-HDL by esterification of cholesterol to cholesteryl esters (CE) by lecithin cholesterol acyltransferase. The hepatic ABCA1 transporter and apoA-I are major determinants of levels of plasma ␣-HDL cholesterol as well as poorly lipidated apoA-I, which interact with ABCA1 transporters on peripheral cells in the process of reverse cholesterol transport. Cholesterol in HDL is transported directly back to the liver by HDL or after transfer of CE by the cholesteryl ester transfer protein (CETP) by the apoB lipoproteins. Current approaches to increasing HDL to determine the efficacy of HDL in reducing atherosclerosis involve acute HDL therapy with infusions of apoA-I or apoA-I mimetic peptides and chronic long-term therapy with selective agents to increase HDL, including CETP inhibitors.

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