ATP-binding cassette transporter AI and its role in HDL formation.
OBJECTIVE
ATP-binding cassette transporter AI (ABCA1)-mediated assembly of phospholipid and free cholesterol with apoA-I plays an important role in HDL biogenesis. This review focuses on recent progress in ABCA1-mediated HDL formation and regulation of ABCA1 expression.


RESULTS
Studies of hepatic ABCA1 overexpression suggest that the liver is a major site for HDL formation. Lipidation of apoA-I by ABCA1 increases its potential for reverse cholesterol transport based on the following findings: (1) apoA-I/lipid complexes formed by ABCA1 are better acceptors of cellular lipid via non-ABCA1-mediated efflux pathways than lipid-free apoA-I in vitro and (2) lipidation of apoA-I prevents it from rapidly associating with plasma HDL in vivo, resulting in more available nascent pre-beta HDL for cellular lipid efflux. Several novel regulatory mechanisms for ABCA1 at the post-transcriptional level have been identified recently. Interaction of apoA-I with ABCA1 prevents phosphorylation of a sequence rich in proline, glutamic acid, serine and threonine in a cytoplasmic domain of ABCA1, resulting in less degradation by calpain proteolysis and increased surface expression of ABCA1. In addition, destabilization and decreased cellular surface expression of ABCA1 protein by unsaturated fatty acids have been identified.


CONCLUSIONS
Initial lipidation of apoA-I by hepatic ABCA1 is critical for plasma HDL formation because it enables pre-beta HDL to function more efficiently as a cholesterol acceptor for other pathways of cholesterol efflux in the reverse cholesterol transport pathway and prevents apoA-I from rapidly associating with preexisting plasma HDL particles, resulting in greater availability of pre-beta HDL particles for cholesterol efflux.
Lee
Ji-Young
JY
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Parks
John S
JS
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000096:biosynthesis*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D008075:Lipoproteins, HDL / Q000096:biosynthesis*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D005227:Fatty Acids; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL