Recent advances in membrane microdomains: Rafts, caveolae, and intracellular cholesterol trafficking

Cellular cholesterol homeostasis is a balance of influx, catabolism and syn thesis, and eff lux. Unlike vascular lipoprotein cholesterol transport, Int racellular cholesterol trafficking is only beginning to be resolved. Exogen ous cholesterol and cholesterol ester enter cells via the low-density lipop rotein (LDL) receptor/ lysosomal and less so by nonvesicular, high-density lipoprotein (HDL) receptor/caveolar pathways. However, the mechanism(s) whe reby cholesterol enters the lysosomal membrane, translocates, and transfers out of the lysosome to the cell interior are unknown. Likewise, the steps whereby cholesterol enters the cytofacial leaflet of the plasma membrane ca veolae, rapidly translocates, leaves the exofacial leaflet, and transfers t o extracellular HDL are unclear. Increasing evidence obtained with model an d isolated cell membranes, transfected cells, genetic mutants, and gene-abl ated mice suggests that proteins such as caveolin, sterol carrier protein-2 (SCP-2), Niemann-Pick C1 protein, steroidogenic acute regulatory protein ( StAR), and other intracellular proteins mediate intracellular cholesterol t ransfer. While these proteins bind cholesterol and/or interact with cholest erol-rich membrane microdomains (e.g., caveolae, rafts, and annuli), their relative contributions to direct molecular versus vesicular cholesterol tra nsfer remain to be resolved. The formation, regulation, and role of membran e microdomains in regulating cholesterol uptake/efflux and trafficking are unclear. Some cholesterol-binding proteins exert opposing effects on cellul ar cholesterol uptake/efflux, transfer of cholesterol out of the lysosomal membrane, and/or intracellular cholesterol trafficking to select membranous organelles. Resolving these cholesterol pathways and the role of membrane cholesterol microdomains is essential to our understanding not only of proc esses that affect cholesterol metabolism, but also of the abnormal regulati on that may lead to disease (diabetes, obesity, atherosclerosis, neutral li pid storage, Niemann-Pick C, congenital lipoid adrenal hyperplasia, etc.).