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Dig Dis Sci (2010) 55:292299 DOI 10.1007/s10620-009-0734-3
ORIGINAL ARTICLE
HMG-CoA Reductase Inhibitors (Statins) Activate Expressionof PPARa/PPARc and ABCA1 in Cultured Gallbladder Epithelial Cells
Jin Lee Eun Mi Hong Dong Hee Koh Min Ho Choi Hyun Joo Jang Sea Hyub Kae Ho Soon Choi
Received: 15 October 2008 / Accepted: 16 January 2009 / Published online: 19 February 2009 Springer Science+Business Media, LLC 2009
Abstract In gallbladder epithelial cells (GBEC), PPARa and PPARc ligands modulate inammation by suppression of TNFa production and prevent excessive accumulation of cholesterol by ABCA1 activation. Recently, HMG-CoA reductase inhibitors (statins) were shown to activate PPARa and PPARc in various cells but no studies of their effects in GBEC have been conducted. The objective of this study was, therefore, to determine the effects of statins on PPAR and ABCA1 expression and the anti-inamma-tory effect of statins in GBEC. Canine GBEC were cultured on Petri dishes. Expression of the proteins PPARa, PPARc, and ABCA1 was measured by western blotting analysis after treatment with simvastatin, pravastatin, NO-pravastatin, PPARa ligand, or PPARc ligand in the culture media. Expression of ABCA1 and LXRa mRNAs was estimated by RT-PCR. Expression of TNFa mRNA was measured by RT-PCR after 24 h pre-treatment with the statins, preceding 1 h of lipopolysaccharide (LPS) loading. Simvastatin, pravastatin, and NO-pravastatin increased expression of the proteins PPARa, PPARc, and ABCA1, and expression of the mRNA of ABCA1 and LXRa in GBEC. Pre-treatment with simvastatin, pravastatin, and NO-pravastatin suppressed the production of TNFa mRNA induced by LPS. In conclusion, statins probably contribute
to the preservation of GBEC function by activation of PPARa and PPARc, which have anti-inammatory effects by suppression of pro-inammatory cytokines, and ABCA1 activation mediated by LXRa, which prevents the accumulation of cholesterol in GBEC.
Keywords HMG-CoA reductase inhibitor (statin)
PPARa PPARc ABCA1 Gallbladder
Introduction
Gallbladder (GB)-associated factors, for example hypomotility, inammation, and mucin secretion, are regarded as major elements of the pathogenesis of gallstones [1, 2]. Accordingly, the modulation of inammation and the elimination of excessive cholesterol in gallbladder epithelial cells (GBEC) can be an important means of preserving GBEC function.
PPARa and PPARc have anti-inammatory effects by blocking the NF-jB pathway in macrophages and bro-blasts [3, 4]. Recently, we demonstrated the existence of PPARa and PPARc in GBEC; we...