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Papers In Press, published online ahead of print March 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700276-JLR200

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Journal of Lipid Research, Vol. 49, 563-571, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Secretory phospholipase A₂ increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion

Uwe J. F. Tietge^1,*,, Niels Nijstad, Rick Havinga, Julius F. W. Baller, Fjodor H. van der Sluijs, Vincent W. Bloks, Thomas Gautier and Folkert Kuipers

^* Department of Medicine, Campus Charité Mitte, Humboldt University, Berlin, Germany
Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures.

Published, JLR Papers in Press, November 25, 2007.

¹ To whom correspondence should be addressed. e-mail: u_tietge{at}yahoo.com

High density lipoprotein cholesterol represents a major source of biliary cholesterol. Secretory phospholipase A₂ (sPLA₂) is an acute phase enzyme mediating decreased plasma HDL cholesterol levels. Clinical studies reported a link between increased sPLA₂ expression and the presence of cholesterol gallstones. The aim of our study was to investigate whether the overexpression of human sPLA₂ in transgenic mice affects biliary cholesterol secretion and gallstone formation. Liver weight (P < 0.01) and hepatic cholesterol content (P < 0.01) were significantly increased in sPLA₂ transgenic mice compared with controls as a result of increased scavenger receptor class B type I (SR-BI)-mediated hepatic selective uptake of HDL cholesterol (P < 0.01), whereas hepatic SR-BI expression remained unchanged. However, biliary cholesterol secretion as well as fecal neutral sterol and fecal bile salt excretion remained unchanged in sPLA₂ transgenic mice. Furthermore, gallstone prevalence in response to a lithogenic diet was identical in both groups. These data demonstrate that i) increased flux of cholesterol from HDL into the liver via SR-BI as a result of phospholipase modification of the HDL particle translates neither into increased biliary and fecal sterol output nor into increased gallstone formation, and ii) increased sPLA₂ expression in patients with cholesterol gallstones might be a consequence rather than the underlying cause of the disease.

Supplementary key words inflammation • reverse cholesterol transport • high density lipoprotein • scavenger receptor class B type I

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