ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice (original) (raw)
Structural snapshot of the cholesterol-transport ABC proteins
Biochemistry and cell biology = Biochimie et biologie cellulaire, 2018
The ATP-binding cassette (ABC) proteins play critical roles in maintaining lipid and sterol homeostasis in higher eukaryotes. In human, several subfamily-A and -G members function as cholesterol transporters across the cellular membranes. Deficiencies of these ABC proteins can cause dyslipidemia that is associated with health conditions such as atherosclerosis, diabetes, fatty liver disease, and neurodegeneration. The physiological roles of ABC cholesterol transporters have been implicated in mediating cholesterol efflux for reverse cholesterol transport and in maintaining membrane integrity for cell survival. The precise role of these ABC transporters in cells remains elusive, and little is known about the sterol-transport mechanism. The membrane constituents of ABC transporters have been postulated to play a key role in determining the transport substrates and the translocation mechanisms via the transmembrane domains. Recent breakthroughs in determining high-resolution structures...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2004
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. (Arterioscler Thromb Vasc Biol. 2004;24:1755-1760.) Key Words: ABCA1 transporter Ⅲ cholesterol Ⅲ cholesteryl ester transfer protein Ⅲ cholesteryl ester transfer protein inhibitor Ⅲ apoA-I
Arteriosclerosis, Thrombosis, and Vascular Biology, 2013
A TP-binding cassette transporter A1 (ABCA1) is a key protein determining high-density lipoprotein (HDL) function. In 1999, it was discovered by 3 independent groups that mutations in the gene for ABCA1 underlie the molecular defect in the HDL deficiency syndrome Tangier disease. Subsequent studies with genetically engineered mice lacking or overexpressing ABCA1 provided evidence that ABCA1 modulates atherosclerosis susceptibility on either end of the reverse cholesterol transport pathway. In the liver (and to a lesser extent in intestine), it determines the biogenesis of nascent HDL particles, whereas in macrophages it is essential for the prevention of the excess cholesterol accumulation by facilitating the transport of cellular cholesterol and phospholipid onto lipid-poor apo AI, the major apoprotein of HDL.
The ABC transporters in lipid flux and atherosclerosis
Progress in Lipid Research, 2011
Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States and in many other countries. Dysfunctional lipid homeostasis plays a central role in the initiation and progression of atherosclerotic lesions. The ATP-binding cassette (ABC) transporters are transmembrane proteins that hydrolyze ATP and use the energy to drive the transport of various molecules across cell membranes. Several ABC transporters play a pivotal role in lipid trafficking. They are critically involved in cholesterol and phospholipid efflux and reverse cholesterol transport (RCT), processes that maintain cellular cholesterol homeostasis and protect arteries from atherosclerosis. In this article we provide a review of the current literature on the biogenesis of ABC transporters and highlight their proposed functions in atheroprotection.
ABC transporters, atherosclerosis and inflammation
Atherosclerosis, 2010
Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier Disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.
Hepatobiliary cholesterol transport is not impaired in ABCA1 null mice
Gastroenterology, 2001
The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1 -/-, Abca1 +/-, and Abca1 +/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1 -/mice were indistinguishable from those in Abca1 +/and Abca1 +/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1 -/mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.
The Journal of Lipid Research, 2003
Apolipoproteins, such as apolipoprotein A-I (apoA-I), can stimulate cholesterol efflux from cells expressing the ATP binding cassette transporter A1 (ABCA1). The nature of the molecular interaction between these cholesterol acceptors and ABCA1 is controversial, and models suggesting a direct protein-protein interaction or indirect association have been proposed. To explore this issue, we performed competition binding and chemical cross-linking assays using six amphipathic plasma proteins and an 18 amino acid amphipathic helical peptide. All seven proteins stimulated lipid efflux and inhibited the cross-linking of apoA-I to ABCA1. Cross-linking of apoA-I to ABCA1 was saturable and occurred at high affinity ( K d of 7.0 ؎ 1.9 nM), as was cross-linking of apoA-II. After binding to ABCA1, apoA-I rapidly dissociated (half-life of 25 min) from the complex and was released back into the medium. A mutant form of ABCA1 (W590S) that avidly binds apoA-I but fails to promote cholesterol efflux released apoA-I with similar kinetics but without transfer of cholesterol to apoA-I. Thus, a highaffinity, saturable, protein-protein interaction occurs between ABCA1 and all of its amphipathic protein ligands. Dissociation of the complex leads to the cellular release of cholesterol and the apolipoprotein. However, dissociation is not dependent on cholesterol transfer, which is a clearly separable event, distinguishable by ABCA1 mutants. -Fitzgerald, M. L., A. L. Morris, A. Chroni, A. J. Mendez, V. I. Zannis, and M. W. Freeman. ABCA1 and amphipathic apolipoproteins form high-affinity molecular complexes required for cholesterol efflux. J. Lipid Res. 2004. 45: 287-294.
Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL
Journal of Clinical Investigation, 2001
The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1-/-, Abca1 +/-, and Abca1 +/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1-/mice were indistinguishable from those in Abca1 +/and Abca1 +/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1-/mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.
Molecular basis of cholesterol efflux via ABCG subfamily transporters
Proceedings of the National Academy of Sciences, 2021
Significance Cholesterol is an essential component of animal cell membranes whose level in cells is maintained within a narrow range. Cholesterol is actively excreted from cells by two ATP-binding cassette (ABC) transporters, ABCG5–ABCG8 (G5G8) in the liver and gut and ABCG1 (G1) in macrophages. The mechanism(s) by which these proteins translocate rigid, planar sterol molecules across the membrane bilayer remain unknown. Here, we report the structure of human G1 and G5G8 in their unbound and cholesterol-bound states. We also determined the structure of G1 bound to ATP. These structures, together with functional studies in model organisms and biochemical studies, identify the binding site for cholesterol and provide the basis for a model of cholesterol transport by ABC transporters.