Abstract
To investigate the role of the peroxisome proliferator-activated receptor-γ (PPARγ) 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. PPARγ activation was performed in LO2 cell by lentivirus transfection and in Caco2 cell by PPARγ 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 PPARγ by pioglitazone prevents cholesterol gallstone formation by increasing biliary BA synthesis and enterohepatic circulation. Activated PPARγ induced the expression of genes involved in enterohepatic circulation and bile acid synthesis (like PCG1α, BSEP, MRP2, MRP3, MRP4, NTCP, CYP7A1, CYP27A1, ASBT, OSTα, and OSTβ). Downregulation of FXR repressed expression of partial genes involved in BA enterohepatic circulation. These findings suggest a new function of PPARγ in preventing CGD by handling BA synthesis and transport through a FXR dependent or independent pathway.
Highlights
Cholesterol gallstone disease (CGD) is a multifactorial disease caused by the interaction of several poorly defined environmental and genetic factors [1]
Pioglitazone treatment significantly slowed down the formation of cholesterol crystals, and no micro gallstones were found in the LM group despite lithogenic diet (LGD) treatment (Figure 1(d))
We found the mRNA expression of Cyp7a1 and Cyp27a1, the two key enzymes in bile acid synthesis, was markedly suppressed in lithogenic diet-fed mice, while pioglitazone restored their expression
Summary
Cholesterol gallstone disease (CGD) is a multifactorial disease caused by the interaction of several poorly defined environmental and genetic factors [1]. Five conditions promote the formation of cholesterol crystals: (1) biliary cholesterol supersaturation due to hypersecretion of cholesterol by the liver [2]; (2) enhanced intestinal cholesterol absorption [2]; (3) relative reduction of BA and phospholipid content in the bile, with resultant decrease in bile hydrophilicity [2]; (4) biliary stasis due to impaired gallbladder motility, accompanied by gallbladder inflammation [3]; and (5) genetic defects [1, 4]. Cholesterol crystals precipitate when the balance among cholesterol, bile acids (BA), and bile phospholipids is disrupted [5]. These crystals keep aggregating and form pathologic gallstones. Since enterohepatic circulation (EHC) plays a fundamental role in the regulation of the synthesis and transport of BA [6], a beneficial regulation of EHC could probably prevent CGD formation
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