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Papers In Press, published online ahead of print November 25, 2007
J. Lipid Res., doi:10.1194/jlr.M700276-JLR200
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Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, Groningen 9713 GZ
Corresponding Author: u_tietge{at}yahoo.com
High density lipoprotein cholesterol (HDL-C) represents a major source of biliary cholesterol. Secretory phospholipase A2 (sPLA2) is an acute phase enzyme promoting HDL catabolism resulting in decreased plasma HDL-C levels. Clinical studies reported a link between increased sPLA2 expression and presence of cholesterol gallstones. The aim of our study was therefore to investigate, whether specific overexpression of human sPLA2 in transgenic mice impacts on 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, due to increased scavenger receptor BI (SR-BI)-mediated hepatic selective uptake of HDL-C (41±3 vs. 30±2 (%cholesteryl ester tracer uptake-%protein tracer uptake)/
Revised on October 30, 2007
Accepted on November 25, 2007
Secretory phospholipase A2 (sPLA2) expression in transgenic mice results in increased hepatic SR-BI-mediated selective HDL cholesteryl ester uptake but does not affect biliary cholesterol secretion or gallstone formation
g liver, p<0.01) and flux of HDL-C into the liver (68±5 vs. 44±3 g/h/liver, p<0.01). Hepatic SR-BI expression remained unchanged, while the overall hepatic gene expression pattern in sPLA2 transgenic mice was consistent with increased cholesterol influx and storage. However, biliary secretion rates of cholesterol, phospholipids and bile salts 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 due to phospholipase modification of the HDL particle neither translates into increased biliary and fecal sterol output nor into increased gallstone formation, (ii) increased sPLA2 expression in patients with cholesterol gallstones might rather be a consequence than the underlying cause of the disease.
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