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Publication : Editor's Highlight: Clofibrate Decreases Bile Acids in Livers of Male Mice by Increasing Biliary Bile Acid Excretion in a PPARĪ±-Dependent Manner.

First Author  Zhang Y Year  2017
Journal  Toxicol Sci Volume  160
Issue  2 Pages  351-360
PubMed ID  28973556 Mgi Jnum  J:273672
Mgi Id  MGI:6282777 Doi  10.1093/toxsci/kfx191
Citation  Zhang Y, et al. (2017) Editor's Highlight: Clofibrate Decreases Bile Acids in Livers of Male Mice by Increasing Biliary Bile Acid Excretion in a PPARalpha-Dependent Manner. Toxicol Sci 160(2):351-360
abstractText  Fibrates and their receptor, namely peroxisome proliferator-activated receptor alpha (PPARalpha), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARalpha activation on BA homeostasis remains controversial. In this study, both wild-type (WT) and PPARalpha-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-term PPARalpha activation on BA homeostasis. Although a decrease in total BAs (SigmaBAs) was observed in livers of CLOF-treated WT mice, it was not observed in PPARalpha-null mice. CLOF-mediated decrease in SigmaBAs in the liver was not likely due to the reduction in BA synthesis or BA uptake, as evidenced by an increase in the BA synthetic enzyme (Cyp7a1) and 2 BA uptake transporters (Na (+)-taurocholate cotransporting polypeptide [Ntcp] and organic anion transporting polypeptide [Oatp]1b2). Instead, the decrease in liver BAs by CLOF is largely a result of increased biliary excretion of BAs, which was associated with a significant induction of the canalicular efflux transporter (bile salt export pump [Bsep]) in the liver. The PPARalpha-mediated increase in Cyp7a1 in CLOF-treated WT mice was not due to farnesoid X receptor (Fxr)-small heterodimer partner (Shp) signaling in the liver, but due to suppression of Fxr- fibroblast growth factor15 signaling in the ileum. Additionally, CLOF also suppressed intestinal BA transporters (apical sodium-dependent bile acid transporter and organic solute transporterbeta) and cholesterol efflux transporters (Abcg5 and Abcg8) in a PPARalpha-dependent manner. In summary, this study provides the first comprehensive analysis on the effect of a short-term CLOF treatment on BA homeostasis, and revealed an essential role of PPARalpha in regulating BA synthesis, transport and signaling.
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