Cell Biology of ABCA1

细胞内胆固醇水平的控制是一个复杂的调控过程，不仅依赖于脂质摄取和细胞甾醇合成的调节，还依赖于允许细胞将胆固醇流出到载脂蛋白和脂蛋白受体分子的机制。这种外排途径在人类生理学中的重要性的最好证据来自对丹吉尔病患者的研究。最近的研究表明，丹吉尔病的遗传缺陷定位于编码ATP结合盒转运体(ABCA1)家族成员之一的一个基因座，该转运体是正常的、载脂蛋白刺激的胆固醇外流所必需的。在体内，当低脂高密度脂蛋白与细胞结合，并至少部分地通过ABCA1介导的过程刺激细胞脂质的去除时，反向胆固醇运输途径被认为是启动的。由于控制胆固醇反向转运途径的药理学工具远不如降低致动脉粥样硬化的脂蛋白水平那么复杂和有效，因此研究ABCA1的S功能所获得的见解有可能导致新的临床治疗方法。在这项提案中，研究人员将探索ABCA1功能背后的结构要求，重点是它的膜拓扑结构、与配体的结合作用以及激酶的调节。这些对ABCA1转运体细胞生物学的研究不仅有助于从分子上描述细胞内胆固醇外流途径，而且有助于我们对维持或破坏人类胆固醇内稳的机制有更深入的了解。

The control of intra-cellular cholesterol levels is an intricately regulated process that depends not only on the regulation of lipid uptake and cellular sterol synthesis but also on a mechanism that permits cells to efflux cholesterol to apolipoprotein and lipoprotein acceptor molecules. The best evidence for the importance of this efflux pathway in human physiology comes from studies of patient's with Tangier disease. Recent work has shown that the genetic defect in Tangier disease maps to a locus encoding a member of the ABCA family of ATP- binding cassette transporters (ABCA1) and that this transporter is required for normal, apolipoprotein-stimulated cholesterol efflux. In vivo, the reverse cholesterol transport pathway is thought to be initiated when a lipid-poor HDL binds to a cell and stimulates the removal of cellular lipids, at least in part, via this ABCA1-mediated process. As the pharmacologic tools for manipulating the reverse cholesterol transport pathway are far less sophisticated and effective than those available for reducing the levels of pro-atherogenic lipoproteins, insights gained from investigating ABCA1's function have the potential to lead to new clinical therapeutics. In this proposal, the investigators will explore the structural requirements that underlie ABCA1 function, focusing on its membrane topology, binding interaction with ligands, and regulation by kinases. These studies of the cell biology of the ABCA1 transporter will importantly contribute not only to a molecular description of the cellular cholesterol efflux pathway but also to our growing understanding of the mechanisms by which human cholesterol homeostasis is maintained or goes awry.