ABCA1 and biogenesis of HDL.
Mammalian somatic cells do not catabolize cholesterol and therefore export it for sterol homeostasis at cell and whole body levels. This mechanism may reduce intracellularly accumulated excess cholesterol, and thereby would contribute to the prevention or cure of the initial stage of atherosclerotic vascular lesion. High-density lipoprotein (HDL) plays a central role in this reaction by removing cholesterol from cells and transporting it to the liver, the major cholesterol catabolic site. Two independent mechanisms have been identified for cellular cholesterol release. The first is non-specific diffusion-mediated cholesterol "efflux" from the cell surface, in which cholesterol is trapped by various extracellular acceptors including lipoproteins. Extracellular cholesterol esterification of HDL provides a driving force for the net removal of cell cholesterol by this pathway, and some cellular factors may enhance this reaction. The other mechanism is an apolipoprotein-mediated process to generate new HDL particles by removing cellular phospholipid and cholesterol. This reaction is mediated by a membrane protein ATP-binding cassette transporter A1 (ABCA1), and lipid-free or lipid-poor helical apolipoproteins recruit cellular phospholipid and cholesterol to assemble HDL particles. The reaction is composed of two elements: the assembly of HDL particles with phospholipid by apolipoprotein, and cholesterol enrichment in HDL. ABCA1 is essential for the former step and the latter requires further intracellular events. ABCA1 is a rate-limiting factor of HDL assembly and is regulated by transcriptional and post-transcriptional factors. Post-transcriptional regulation of ABCA1 involves modulation of its calpain-mediated degradation.
Yokoyama
Shinji
S
Biochemistry, Cell Biology and Metabolism, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan. syokoyam@med.nagoya-cu.ac.jp
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D008076:Cholesterol, HDL / Q000378:metabolism*; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D006801:Humans
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D004247:DNA