University of Groningen Secretory phospholipase A ( 2 ) increases SRB 1-mediated selective uptake from HDL but not biliary cholesterol secretion

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. —Tietge, U. J. F. , N. Nijstad, R. Havinga, J. F. W. Baller, F. H. van der Sluijs, V. W. Bloks, T. Gautier, and F. Kuipers. Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion. J. Lipid Res. 2008. 49: 563–571. Supplementary key words inflammation & reverse cholesterol transport & high density lipoprotein & scavenger receptor class B type I The protective effects of HDL against atherosclerotic cardiovascular disease are generally ascribed to the central role of the HDL particle in reverse cholesterol transport (RCT) (1, 2). RCT in this context comprises the ability of HDL to mediate the transport of excess cholesterol from lipid-laden macrophages within the vascular wall back to the liver for excretion into the bile, which represents the major route for irreversible removal of cholesterol from the body. The acute phase protein secretory group IIA phospholipase A2 (sPLA2) is a low molecular mass (14 kDa) enzyme with exclusive phospholipase activity hydrolyzing phospholipids at the sn -2 position (3, 4). Compared with wildtype C57BL/6 controls that lack the endogenous mouse sPLA2 enzyme as a result of a frameshift mutation (5), human sPLA2 transgenic mice have significantly decreased plasma HDL cholesterol levels, suggesting that sPLA2 is a major mediator of the decreased plasma HDL cholesterol invariably associated with acute as well as chronic inflammatory states (6–8). Patients with chronic inflammatory diseases have a higher risk of developing atherosclerotic cardiovascular disease (9, 10), and sPLA2 transgenic mice develop atherosclerotic lesions even on a chow diet (11). On the other hand, atherosclerosis itself is increasingly recognized as a localized inflammatory condition within the vessel wall (12, 13). The pathophysiological significance of sPLA2 in this respect is underlined by studies demonstrating increased circulating plasma levels of sPLA2 to be predictive for acute coronary events (14–16). The scavenger receptor class B type I (SR-BI) has been identified as a key component in RCT mediating the selective uptake of HDL cholesterol by the liver for subsequent biliary excretion (17, 18). SR-BI knockout mice and mice with attenuated hepatic SR-BI expression have increased plasma HDL cholesterol levels and decreased biliary cholesterol levels (19, 20). In contrast, hepatic overexpression of SR-BI results in decreased plasma HDL Manuscript received 13 June 2007 and in revised form 30 October 2007. Published, JLR Papers in Press, November 25, 2007. DOI 10.1194/jlr.M700276-JLR200 To whom correspondence should be addressed. e-mail: u_tietge@yahoo.com The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two figures. Copyright D 2008 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr. org Journal of Lipid Research Volume 49, 2008 563 at U nirsity of G ronngen, on Jauary 3, 2017 w w w . j.org D ow nladed fom 0.DC1. html http://www.jlr. org/content/suppl/2007/11/28/M700276-JLR20 Supplemental Material can be found at: