HDL apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol.
It is widely believed that HDL protects against atherosclerosis by removing excess cholesterol from arterial cells. Lipid-poor HDL apolipoproteins promote efflux of cholesterol, phospholipids, and other lipophilic molecules from cells by an active process mediated by a cell-membrane transporter called the ATP binding cassette transporter A-1 (ABCA1). ABCA1 either directly or indirectly translocates phospholipids and cholesterol to the cell surface, where they appear to form lipid domains that interact with amphipathic alpha-helixes in apolipoproteins. This interaction solubilizes these lipids and generates nascent HDL particles that dissociate from the cell. Binding of apolipoproteins to ABCA1 may also enhance the activity of this lipid-transport pathway. Thus, the apolipoprotein/ABCA1 pathway efficiently clears cells of excess cholesterol that would otherwise accumulate as intracellular lipid droplets. ABCA1 expression is highly induced by cholesterol loading of cells and is also modulated by sterol-independent mechanisms at both the transcriptional and posttranslational level. Studies of human disease and animal models have shown that both an increased availability of apolipoproteins and an enhanced macrophage ABCA1 activity are atheroprotective. These findings implicate the apolipoprotein/ABCA1 pathway as an important therapeutic target for treating cardiovascular disease.
Oram
John F
JF
Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195, USA. joram@u.washington.edu
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000502:physiology*; D000595:Amino Acid Sequence; D001692:Biological Transport; D018955:CD36 Antigens / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology*; D008565:Membrane Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D010743:Phospholipids; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol