title: Molecular mechanism of reverse cholesterol transport: reaction of pre-beta-migrating high-density lipoprotein with plasma lecithin/cholesterol acyltransferase.
abstract: A 70-75 kDa high-density lipoprotein (HDL) particle with pre-beta-electrophoretic migration (pre-beta(1)-HDL) has been identified in several studies as an early acceptor of cell-derived cholesterol. However, the further metabolism of this complex has not been determined. Here we sought to identify the mechanism by which cell-derived cholesterol was esterified and converted to mature HDL as part of reverse cholesterol transport (RCT). Human plasma selectively immunodepleted of pre-beta(1)-HDL was used to study factors regulating pre-beta(1)-HDL production. A major role for phospholipid transfer protein (PLTP) in the recycling of pre-beta(1)-HDL was identified. Cholesterol binding, esterification by lecithin/cholesterol acyltransferase (LCAT) and transfer by cholesteryl ester transfer protein (CETP) were measured using (3)H-cholesterol-labeled cell monolayers. LCAT bound to (3)H-free cholesterol (FC)-labeled pre-beta(1)-HDL generated cholesteryl esters at a rate much greater than the rest of HDL. The cholesteryl ester produced in pre-beta(1)-HDL in turn became the preferred substrate of CETP. Selective LCAT-mediated reactivity with pre-beta(1)-HDL represents a novel mechanism increasing the efficiency of RCT.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Leila
authors.initials: L
authors.lastname: Kotite
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Gan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Spencer
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fielding
authors.forename: Phoebe E
authors.initials: PE
authors.lastname: Fielding
mesh_terms: D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism*; D053442:High-Density Lipoproteins, Pre-beta; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D008565:Membrane Proteins / Q000097:blood / Q000378:metabolism; D008956:Models, Chemical; D008970:Molecular Weight; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood* / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000378:metabolism; D021381:Protein Transport
chemical_list: D016632:Apolipoprotein A-I; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D006023:Glycoproteins; D053442:High-Density Lipoproteins, Pre-beta; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D049294:Phospholipid Transfer Proteins; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase