Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body.
Most mammalian somatic cells are unable to catabolize cholesterol and therefore need to export it in order to maintain sterol homeostasis. This mechanism may also function to reduce excessively accumulated cholesterol, which would thereby contribute to prevention or cure of the initial stage of atherosclerotic vascular lesion. High-density lipoprotein (HDL) has been believed to play a main role in this reaction based on epidemiological evidence and in vitro experimental data. At least two independent mechanisms are identified for this reaction. One is non-specific diffusion-mediated cholesterol 'efflux' from cell surface. Cholesterol molecules desorbed from cells can be trapped by various extracellular acceptors including various lipoproteins and albumin, and extracellular cholesterol esterification mainly on HDL may provide a driving force for the net removal of cell cholesterol by maintaining a cholesterol gradient between lipoprotein surface and cell membrane. The other is apolipoprotein-mediated process to generate new HDL by removing cellular phospholipid and cholesterol. The reaction is initiated by the interaction of lipid-free or lipid-poor helical apolipoproteins with cellular surface resulting in assembly of HDL particles with cellular phospholipid and incorporation of cellular cholesterol into the HDL being formed. Thus, HDL has dual functions as an active cholesterol acceptor in the diffusion-mediated pathway and as an apolipoprotein carrier for the HDL assembly reaction. The impairment of the apolipoprotein-mediated reaction was found in Tangier disease and other familial HDL deficiencies to strongly suggest that this is a main mechanism to produce plasma HDL. The causative mutations for this defect was identified in ATP binding cassette transporter protein A1, as a significant step for further understanding of the reaction and cholesterol homeostasis.
Yokoyama
S
S
Biochemistry 1, Nagoya City University Medical School, Kawasumi 1, Mizuho-cho, Mizuho-ku, 467-8601, Nagoya, Japan. syokoyam@med.nagoya-cu.ac.jp
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D004058:Diffusion; D006706:Homeostasis; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D013631:Tangier Disease / Q000235:genetics / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol