ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells
| Autor: | Shui-Pang Tam, Monika Vasa, Giovanna Chimini, Leo Mok, Roger G. Deeley |
|---|---|
| Přispěvatelé: | Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2006 |
| Předmět: |
Embryo
Nonmammalian Insecta Physiology ATP-binding cassette transporter MESH: Hydroxycholesterols Mice chemistry.chemical_compound MESH: Insects Adenosine Triphosphate MESH: Adenosine Triphosphate polycyclic compounds MESH: Animals Phospholipids Feedback Physiological Reverse cholesterol transport Serum Albumin Bovine Cell biology Biochemistry MESH: ATP-Binding Cassette Transporters [SDV.IMM]Life Sciences [q-bio]/Immunology lipids (amino acids peptides and proteins) Efflux Hydrophobic and Hydrophilic Interactions ATP Binding Cassette Transporter 1 MESH: Mutation Oxysterol Phospholipid Biology Transfection Cell Line MESH: Transport Vesicles Animals Humans Transport Vesicles MESH: Mice MESH: Phospholipids MESH: Hydrophobicity MESH: Humans MESH: Transfection MESH: Feedback Biochemical MESH: Embryo Transporter Cell Biology Fibroblasts Embryo Mammalian Hydroxycholesterols MESH: Cell Line MESH: Hydroxymethylglutaryl CoA Reductases Receptors LDL chemistry MESH: Receptors LDL MESH: Fibroblasts ABCA1 Mutation biology.protein ATP-Binding Cassette Transporters Hydroxymethylglutaryl CoA Reductases MESH: Serum Albumin Bovine |
| Zdroj: | American Journal of Physiology-Cell Physiology American Journal of Physiology-Cell Physiology, American Physiological Society, 2006, 291 (3), pp.C490-502. ⟨10.1152/ajpcell.00055.2006⟩ American Journal of Physiology-Cell Physiology, 2006, 291 (3), pp.C490-502. ⟨10.1152/ajpcell.00055.2006⟩ |
| ISSN: | 1522-1563 0363-6143 |
| DOI: | 10.1152/ajpcell.00055.2006 |
| Popis: | ATP Binding Cassette (ABC) transporter, ABCA1, plays a pivotal role in reverse cholesterol transport by mediating the cellular efflux of phospholipid and cholesterol. Studies using intact cells strongly suggest that ABCA1 acts as a phospholipid floppase, but there has been no direct demonstration that the protein is a primary active sterol transporter. Using membrane vesicles from insect Sf21 cells, we found that ABCA1 mediated ATP-dependent uptake of [3H]25-hydroxycholesterol with an apparent Kmof 0.7 μM. Consistent with this high apparent affinity, expression of ABCA1 in human embryonic kidney cells both increased rapid efflux of 25-hydroxcholesterol and prevented oxysterol-mediated repression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNAs. Comparison of wild-type and ABCA1−/−murine fibroblasts indicates that 25-hydroxycholesterol is effluxed ∼5-fold more rapidly by wild-type cells. In addition, the rate of efflux from the wild-type but not the ABCA1−/−fibroblasts is increased a further twofold by inducers of ABCA1 expression. Thus under the experimental conditions employed, endogenous ABCA1 is a major contributor to 25-hydroxycholesterol efflux from wild-type fibroblasts. Evidence from in vitro studies indicates that oxysterols are potent inducers of genes involved in cellular cholesterol efflux and metabolism, including the ABCA1 gene, and repressors of genes involved in cholesterol synthesis or uptake. Our observations raise the possibility that efflux of oxysterols by ABCA1 could contribute to a homeostatic mechanism, which both attenuates oxysterol-induced expression of its cognate gene and alleviates repression of genes encoding proteins, such as HMG-CoA reductase and LDL receptor. |
| Databáze: | OpenAIRE |
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