Review
The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes

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Abstract

ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that exports cholesterol from cells and suppresses macrophage inflammation. ABCA1 exports cholesterol by a multistep pathway that involves forming cell-surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Thus, ABCA1 behaves both as a lipid exporter and a signaling receptor. ABCA1 transcription is highly induced by sterols, and its expression and activity are regulated post-transcriptionally by diverse processes. ABCA1 mutations can reduce plasma HDL levels, accelerate cardiovascular disease, and increase the risk for type 2 diabetes. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels, inflammation, atherogenesis, and pancreatic β cell function. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages, raising the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become a promising new therapeutic target for treating cardiovascular disease and diabetes.

Introduction

Cholesterol is an abundant metabolite in mammalian tissues that is essential for several biological systems. Membrane fluidity of all cells is controlled by the ordered packing of cholesterol between phospholipid molecules. Cholesterol also concentrates in sphingolipid-rich domains of the plasma membrane called rafts that contain a variety of important receptors and signaling molecules [1]. In addition, cholesterol is a substrate for steroid production and covalently links to a cell morphogen required for normal embryonic development and cell differentiation [2]. Too much cholesterol, however, can have pathological consequences. Because cholesterol is poorly soluble in water and seeks a lipid environment, an uncontrolled build up of cholesterol in cells can disrupt membranes and cause cytotoxicity [3]. Accumulation of excess cholesterol causes atherosclerotic cardiovascular disease (CVD) [4] and might contribute to the early onset of Alzheimer's disease [5] and renal dysfunction [6], [7]. Cells therefore rely on a complex homeostatic network to modulate the availability of cholesterol.

Cells other than those in steroidogenic tissues and the liver cannot catabolize cholesterol. Instead they modulate their membrane cholesterol content by a feedback system that controls the rate of cholesterol biosynthesis and uptake by the low-density lipoprotein (LDL) receptor. With most cell types this system is sufficient to provide cells with enough cholesterol for cellular functions without overloading them. Macrophages, however, can ingest membrane- or lipoprotein-derived cholesterol by endocytotic and phagocytotic pathways that are not feedback regulated by cholesterol. These cells must either store this excess cholesterol as esters in lipid droplets or export it.

A subfraction of circulating lipoproteins called high-density lipoproteins (HDLs) is involved in the export of excess cholesterol from cells. One of the major functions of HDL is to transport cholesterol from peripheral tissues to the liver for elimination in the bile [8]. It is believed that the removal of excess cholesterol from arterial macrophages contributes to the well-established cardioprotective effects of HDL.

HDL components can remove cellular cholesterol by multiple mechanisms [9]. HDL phospholipids absorb cholesterol that diffuses from the plasma membrane into the aqueous phase, a passive process that is facilitated by the interaction of HDL particles with scavenger receptor B1. Three cell membrane transporters have been identified that mediate cholesterol efflux from cells to HDL components by metabolically active pathways. All three belong to a superfamily of ATP-binding cassette transporters (ABCs) [10]. ABCA1 mediates the transport of cellular cholesterol, phospholipids, and other metabolites to HDL proteins (apolipoproteins) that are associated with no or very little lipid [11], [12], [13], [14]. ABCA1 is highly expressed in the liver and tissue macrophages. ABCG1 and ABCG4 mediate cholesterol transport from cells to HDL particles and other lipoproteins [15], [16], [17], [18], [19]. ABCG1 is also highly expressed in macrophages and may work synergistically with ABCA1 to remove excess cholesterol [19], [20]. ABCG4 appears to be selectively expressed in brain cells where it may have a specialized lipid transport function [16].

ABCA1 is one of the most extensively characterized ABC transporters. Numerous studies of cultured cells, human HDL deficiencies, and animal models have shown that ABCA1 is an efficient exporter of cholesterol from macrophages and other cells, a major determinant of plasma HDL levels, and a potent cardioprotective factor. This transporter has therefore become a new therapeutic target for drug development designed for clearing cholesterol from arterial macrophages and preventing CVD. This review will focus on the biology and pathophysiology of ABCA1.

Section snippets

Structure and function

ABCA1 is a 2261-amino-acid integral membrane protein that comprises two halves of similar structure (Fig. 1) [21]. Each half has a transmembrane domain containing six helices and a nucleotide binding domain (NBD) containing two conserved peptide motifs known as Walker A and Walker B, which are present in many proteins that utilize ATP, and a Walker C signature unique to ABC transporters [10]. ABCA1 is predicted to have an N-terminus oriented into the cytosol and two large extracellular loops

Gene variants

Over 70 mutations in ABCA1 have been identified in subjects with low plasma HDL levels, more than half of which are missense mutations [96], [97], [98], [99]. Although these mutations occur throughout the gene, they tend to cluster in the extracellular loops, the NBD domains, and the C-terminal region.

The initial loss-of-function mutations in ABCA1 were discovered in case reports and family studies. More recently, rare and common gene variations were identified by screening ABCA1 from subjects

Pharmacology

The studies described above have provided strong evidence that ABCA1 plays an important role in protection against CVD, metabolic syndrome, and type 2 diabetes, the most common debilitating diseases in the Western world. ABCA1 has therefore become a promising new therapeutic target for these disorders, and multiple programs have been initiated by the pharmaceutical industry to develop agonists for this pathway. These programs are based on the assumption that an increased ABCA1 activity in

Conclusions and future directions

Studies of human HDL deficiencies, transgenic mice, and cultured cells have shown that ABCA1 is the major exporter of cellular cholesterol and phospholipids to HDL apolipoproteins, and that this activity is essential for formation of HDL particles in vivo. There is emerging evidence that ABCA1 also plays a role in suppressing inflammatory cytokine production by macrophages through multiple mechanisms. ABCA1 is unique among transporters in that its interaction with apolipoproteins has

Acknowledgements

The authors' work described in this review was supported by National Institutes of Health grants HL18645, HL075340, HL55362, and DK02456.

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