Mechanism of ATP-binding Cassette Transporter A1-mediated Cellular Lipid Efflux to Apolipoprotein A-I and Formation of High Density Lipoprotein Particles

Charulatha Vedhachalam,Phu T Duong,Margaret Nickel,David Nguyen,Padmaja Dhanasekaran,Hiroyuki Saito,George H Rothblat,Sissel Lund-Katz,Michael C Phillips

doi:10.1074/jbc.m704590200

Abstract

The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the biogenesis of high density lipoprotein (HDL) particles and in mediating cellular cholesterol efflux. The mechanism by which ABCA1 achieves these effects is not established, despite extensive investigation. Here, we present a model that explains the essential features, especially the effects of ABCA1 activity in inducing apolipoprotein (apo) A-I binding to cells and the compositions of the discoidal HDL particles that are produced. The apo A-I/ABCA1 reaction scheme involves three steps. First, there is binding of a small regulatory pool of apo A-I to ABCA1, thereby enhancing net phospholipid translocation to the plasma membrane exofacial leaflet; this leads to unequal lateral packing densities in the two leaflets of the phospholipid bilayer. Second, the resultant membrane strain is relieved by bending and by creation of exovesiculated lipid domains. The formation of highly curved membrane surface promotes high affinity binding of apo A-I to these domains. Third, this pool of bound apo A-I spontaneously solubilizes the exovesiculated domain to create discoidal nascent HDL particles. These particles contain two, three, or four molecules of apo A-I and a complement of membrane phospholipid classes together with some cholesterol. A key feature of this mechanism is that membrane bending induced by ABCA1 lipid translocase activity creates the conditions required for nascent HDL assembly by apo A-I. Overall, this mechanism is consistent with the known properties of ABCA1 and apo A-I and reconciles many of the apparently discrepant findings in the literature.

Highlights

Since the discovery that mutations in the ABCA12 gene are responsible for Tangier disease and low circulating levels of high density lipoprotein (HDL), the ATP-binding cassette transporter A1 (ABCA1) system has been the subject of extensive research activity
HDL is anti-atherogenic, at least in part, because it can participate in reverse cholesterol transport, the process by which excess cholesterol in peripheral cells is returned to the liver for catabolism (5, 6, 8 –10)
The mechanism of the active ABCA1-mediated efflux of cellular lipids to apo A-I has been proposed variously to involve 1) binding of apo A-I either directly to ABCA1 or indirectly to a lipid site created by ABCA1 activity, 2) either simultaneous or sequential release of membrane phospholipid and cholesterol to apo A-I, and 3) assembly of nascent HDL particles either at the cell surface or at intracellular sites during the retroendocytosis of ABCA1

Summary

Introduction

Since the discovery that mutations in the ABCA12 gene are responsible for Tangier disease and low circulating levels of HDL, the ABCA1 system has been the subject of extensive research activity. We present a model that explains the essential features, especially the effects of ABCA1 activity in inducing apolipoprotein (apo) A-I binding to cells and the compositions of the discoidal HDL particles that are produced.

Results

Conclusion