ATVB In Focus
Role of ABCA1 in Cellular Cholesterol Efflux and Reverse Cholesterol Transport
About 30 years ago, John Glomset1 outlined the reverse cholesterol transport hypothesis, proposing that HDL and LCAT might have anti-atherogenic functions related to their ability to transport cholesterol from peripheral tissues to the liver for excretion. As the different molecules and pathways mediating the various steps of reverse cholesterol transport have been discovered, this hypothesis has been sustained and refined. Much remains to be learned, particularly in relation to molecular mechanisms, regulation, and metabolic integration of the different steps of reverse cholesterol transport. The plot is already thick but undoubtedly there are many new molecular players waiting in the wings. A particular challenge is to manipulate reverse cholesterol transport therapeutically in a way that will reduce atherosclerosis and its complications.
See pages 712 and 720
This review series has been inspired by the discovery in 1999 by three different laboratories (led by Bodzioch et al,2 Rust et al,3 and Brooks-Wilson et al4) that Tangier Disease is caused by mutations in the ATP binding cassette transporter ABCA1, providing a new molecular key to understanding the mechanisms and regulation of cellular cholesterol efflux. In the first piece in the series, Yancey and colleagues5 from the Rothblat and Philips laboratory will describe three different pathways that may mediate cellular cholesterol efflux: aqueous diffusion, scavenger receptor BI (SR-BI)–mediated efflux, and active cholesterol efflux mediated by ABCA1. Their review will discuss in detail various potential mechanisms that may be responsible for cholesterol efflux mediated by SR-BI or ABCA1, and the potential metabolic integration of SR-BI and ABCA1 pathways. Oram6 will then describe the role of apolipoproteins and ABCA1 as partners in cellular cholesterol efflux, and summarize the evidence that upregulating either apolipoproteins or ABCA1 are likely to be therapeutically beneficial. Although the mechanisms of ABCA1-mediated lipid efflux remain poorly understood, a common view emerging from both reviews is that ABCA1 likely acts directly or indirectly as a lipid translocase favoring the accumulation of phospholipids and cholesterol in the outer membrane hemileaflet, and that binding of apolipoprotein A-I to ABCA1, as well as to this lipid “patch,” is likely to be involved in lipid efflux and the formation of nascent HDL.
The next two reviews in the series will be focused on transgenic mouse models of ABCA1. Aiello et al7 summarize the findings on ABCA1 gene knockout mice in which the key role of ABCA1 in HDL and apolipoprotein B-lipoprotein metabolism recapitulates many of the features of Tangier Disease. The complex relationship of ABCA1 to atherosclerosis will be described, discrepancies of results between different laboratories will be discussed, and the clear evidence showing an anti-atherogenic role of macrophage ABCA1 will be presented. Joyce and colleagues8 from the National Institutes of Health group review the information that has been gleaned from mice overexpressing human ABCA1, summarizing the key effects on HDL metabolism and discussing the conflicting reports that have appeared on the relationship of ABCA1 overexpression to atherogenesis.
LXR/RXR target many of the key molecules mediating cellular cholesterol efflux, transport, and excretion. A notable target of these transcription factors is ABCA1. LXR/RXR agonists are anti-atherogenic in mouse models, but they also cause fatty liver and hypertriglyceridemia. Lund et al9 discuss the pharmaceutical development of LXR activators and make some shrewd speculations concerning the likely phenotype of LXR activation in humans. They also present several strategies that could be successful in avoiding the induction of fatty acid synthesis while maintaining desirable features of LXR activation. In addition to transcriptional regulation, ABCA1 shows major regulation on a post-transcriptional level. Wang and Tall10 will review recent information on the post-transcriptional stabilization of ABCA1 by apolipoprotein A-I and the role of calpain proteases in the degradation of ABCA1 protein. This review introduces some new ideas on the potential therapeutic modulation of ABCA1.
In the final piece in the series, Hayden and coworkers11 will review what we have learned from mutations in ABCA1 concerning the role of ABCA1 in human lipoprotein metabolism and atherogenesis.
- ↵Glomset JA. The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res. 1968; 9: 155–167.
- ↵Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnick W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet. 1999; 22: 347–351.
- ↵Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensor CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K. Koop B, Primstone S, Kastelein JJ, Hayden MR, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22; 336–345.
- ↵Yancey PG, Bortnick AE, Kellner-Weibel G, de la Ller-Moya M, Phillips MC, Rothblat GH. importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol. 2003; 23: 712–719.
- ↵Oram J. HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol. Arterioscler Thromb Vasc Biol. 2003; 23: 720–727.
- ↵Aiello RJ, Brees D, Francone OL. ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL formation and inflammation. Arterioscler Thromb Vasc Biol. In press.
- ↵Joyce C, Freeman L, Brewer HB Jr, Santamarina-Fojo S. Study of ABCA1 function in transgenic mice. Arterioscler Thromb Vasc Biol. In press.
- ↵Lund EG, Menke JG, Sparrow CP. Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol. In press.
- ↵Wang N, Tall AR. The role of apolipoprotein binding in the function and regulation of ABCA1. Arterioscler Thromb Vasc Biol. In press.
- ↵Hayden MR, Singaraja R, Brunham L, Visscher H. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol. In press.