title: Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile.
abstract: While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[(3)H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [(3)H]cholesterol from HDL-[(3)H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2(-/-) mice. Increased flux of HDL-[(3)H]CE to biliary FC was noted with FABP1 overexpression and in SCP2(-/-) mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[(3)H]CE to biliary FC or bile acids in FABP1(-/-) mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination.
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Bie
authors.affiliation: Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23298 shobha@vcu.edu.
authors.forename: Shobha
authors.initials: S
authors.lastname: Ghosh
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006868:Hydrolysis; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; C072087:sterol carrier proteins; D002784:Cholesterol
keywords: bile acid secretion; cholesterol elimination; cholesteryl esters; fatty acid binding protein-1; hepatocyte; high density lipoprotein; reverse cholesterol transport; sterol carrier protein 2