Pxr Prevents Cholesterol Gallstone Disease By Affecting Bile Acid Biosynthesis And Transport

Cholesterol gallstone disease (CGD), one of the most prevalent and costly digestive diseases, is resulted from biochemical imbalance of lipids and bile salts in the gallbladder bile. In this report, we showed that the previously known “xenobiotic receptor” pregnane X receptor (PXR) plays an important role in preventing CGD. Loss of PXR sensitized mice to lithogenic diet-induced CGD, which was associated with decreased biliary concentrations of bile salts and phospholipids, leading to an increased cholesterol saturation index (CSI) and formation of cholesterol crystals. The decreased bile acid pool size in lithogenic diet-fed PXR−/− mice was associated with a major suppression of Cyp7a1, the ratelimiting enzyme of cholesterol catabolism and bile acid formation. In contrast, treatment of C57L mice with the PXR agonist pregnenolone-16alpha-carbonitrile (PCN) prevented cholesterol precipitation by increasing biliary bile salt concentration and reducing CSI. The benefit of PXR in preventing CGD was achieved by its coordinate regulation of the biosynthesis and transport of bile salts in the liver and intestine. The current findings demonstrate an important role of PXR in maintaining biliary bile acid homeostasis, and establish PXR as a potential therapeutic target for cholesterol gallstone disease.