Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efflux.
ATP-binding cassette transporter A1 (ABCA1) plays a major role in cholesterol homeostasis and HDL metabolism. ABCA1 mediates cellular cholesterol and phospholipid efflux to lipid-poor apolipoproteins, and upregulation of ABCA1 activity is antiatherogenic. ApoA-I, the major apolipoprotein component of HDL, promotes ABCA1-mediated cholesterol and phospholipid efflux, probably by directly binding to ABCA1. ABCA1 gene expression is markedly increased in cholesterol-loaded cells as a result of activation of LXR/RXR. ABCA1 protein turnover is rapid. ABCA1 contains a PEST--proline (P), glutamate (E), serine (S), and threonine (T)--sequence in the intracellular segment that mediates ABCA1 degradation by a thiol protease, calpain. ApoA-I and apoE stabilize ABCA1 in a novel mode of regulation by decreasing PEST sequence-mediated calpain proteolysis. ABCA1-mediated cholesterol and phospholipid efflux are distinctly regulated and affected by the activity of other gene products. Stearyol CoA desaturase decreases ABCA1-mediated cholesterol efflux but not phospholipid efflux, likely by decreasing the cholesterol pool available to ABCA1. This and other evidence suggest that ABCA1 promotes cholesterol and phospholipid efflux, probably by directly transporting both lipids as substrates.
Wang
Nan
N
Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168 Street, New York, NY 10032, USA. nw30@columbia.edu
Tall
Alan R
AR
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013631:Tangier Disease / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; C516738:PTPN12 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D017027:Protein Tyrosine Phosphatases