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Papers In Press, published online ahead of print August 1, 2009
J. Lipid Res., doi:10.1194/jlr.M800434-JLR200

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Journal of Lipid Research, Vol. 50, 1571-1580, August 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice^1,[S]

Harmen Wiersma¹, Alberto Gatti, Niels Nijstad, Folkert Kuipers and Uwe J. F. Tietge²

Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

² To whom correspondence should be addressed. e-mail: u_tietge{at}yahoo.com

High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)–mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.

Supplementary key words bile • EL • HDL • liver • LXR • metabolism • phospholipase • SREBP

Abbreviations: AdhEL, recombinant adenovirus; AdNull, empty adenovirus; EL, endothelial lipase; NS, not significant; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B type I; SREBP, sterol-regulatory element binding protein

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