HMG-CoA Reductase Inhibitors (Statins) Activate Expression of PPAR alpha/PPAR gamma and ABCA1 in Cultured Gallbladder Epithelial Cells

Abstract

In gallbladder epithelial cells (GBEC), PPAR alpha and PPAR gamma ligands modulate inflammation by suppression of TNF alpha production and prevent excessive accumulation of cholesterol by ABCA1 activation. Recently, HMG-CoA reductase inhibitors (statins) were shown to activate PPAR alpha and PPAR gamma 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-inflammatory effect of statins in GBEC. Canine GBEC were cultured on Petri dishes. Expression of the proteins PPAR alpha, PPAR gamma, and ABCA1 was measured by western blotting analysis after treatment with simvastatin, pravastatin, NO-pravastatin, PPAR alpha ligand, or PPAR gamma ligand in the culture media. Expression of ABCA1 and LXR alpha mRNAs was estimated by RT-PCR. Expression of TNF alpha 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 PPAR alpha, PPAR gamma, and ABCA1, and expression of the mRNA of ABCA1 and LXR alpha in GBEC. Pre-treatment with simvastatin, pravastatin, and NO-pravastatin suppressed the production of TNF alpha mRNA induced by LPS. In conclusion, statins probably contribute to the preservation of GBEC function by activation of PPAR alpha and PPAR gamma, which have anti-inflammatory effects by suppression of pro-inflammatory cytokines, and ABCA1 activation mediated by LXR alpha, which prevents the accumulation of cholesterol in GBEC.