Lipid rafts: dream or reality for cholesterol transporters?

As a key constituent of the cell membranes, cholesterol is an endogenous component of mammalian cells of primary importance, and is thus subjected to highly regulated homeostasis at the cellular level as well as at the level of the whole body. This regulation requires adapted mechanisms favoring the handling of cholesterol in aqueous compartments, as well as its transfer into or out of membranes, involving membrane proteins. A membrane exhibits functional properties largely depending on its lipid composition and on its structural organization, which very often involves cholesterol-rich microdomains. Then there is the appealing possibility that cholesterol may regulate its own transmembrane transport at a purely functional level, independently of any transcriptional regulation based on cholesterol-sensitive nuclear factors controling the expression level of lipid transport proteins. Indeed, the main cholesterol "transporters" presently believed to mediate for instance the intestinal absorption of cholesterol, that are SR-BI, NPC1L1, ABCA1, ABCG1, ABCG5/G8 and even P-glycoprotein, all present privileged functional relationships with membrane cholesterol-containing microdomains. In particular, they all more or less clearly induce membrane disorganization, supposed to facilitate cholesterol exchanges with the close aqueous medium. The actual lipid substrates handled by these transporters are not yet unambiguously determined, but they likely concern the components of membrane microdomains. Conversely, raft alterations may provide specific modulations of the transporter activities, as well as they can induce indirect effects via local perturbations of the membrane. Finally, these cholesterol transporters undergo regulated intracellular trafficking, with presumably some relationships to rafts which remain to be clarified.