Peroxisome Proliferator-Activated Receptor-? Prevents Cholesterol Gallstone Formation in C57bl Mice by Regulating Bile Acid Synthesis and Enterohepatic Circulation.

ABSTRACT: To investigate the role of the peroxisome proliferator-activated receptor-? (PPAR?) in the progression of cholesterol gallstone disease (CGD), C57bl/6J mice were randomized to the following groups (n=7/group): L (lithogenic diet, LGD), LM (LGD+pioglitazone), CM (chow diet+pioglitazone), and NC (normal control, chow diet). Gallbladder stones were observed by microscopy. Histological gallbladder changes were assessed. Bile acids (BA) and cholesterol were measured in the serum, bile, and feces. Proteins and mRNA expression of genes involved in BA metabolism and enterohepatic circulation were assessed by western blotting and real-time RT-PCR. PPAR? activation was performed in LO2 cell by lentivirus transfection and in Caco2 cell by PPAR? agonist treatment. Downregulation of farnesoid X receptor (FXR) by small interference RNA (siRNA) was performed in L02 cells and Caco2 cells, respectively. Results showed that pharmacological activation of PPAR? by pioglitazone prevents cholesterol gallstone formation by increasing biliary BA synthesis and enterohepatic circulation. Activated PPAR? induced the expression of genes involved in enterohepatic circulation and bile acid synthesis (like PCG1?, BSEP, MRP2, MRP3, MRP4, NTCP, CYP7A1, CYP27A1, ASBT, OST?, and OST?). Downregulation of FXR repressed expression of partial genes involved in BA enterohepatic circulation. These findings suggest a new function of PPAR? in preventing CGD by handling BA synthesis and transport through a FXR dependent or independent pathway.

SUBMITTER: Wang G 

PROVIDER: S-EPMC6076980 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature