LAUSR

BACKGROUND & AIMS Cholesterol gallstone disease (CGD) is a common gastrointestinal disease. Liraglutide, an analog of glucagon-like peptide 1, has been approved to treat type 2 diabetes. Clinical studies have suggested a potential role of liraglutide in CGD. METHODS Mice were subcutaneously injected with liraglutide, then fed a lithogenic diet. Bile duct cannulation was performed to collect bile output in mice. Intestinal-specific ablation or pharmacological inhibition of farnesoid X receptor (FXR) was used to study its functions in CGD. RESULTS Liraglutide could protect mice against CGD. Liraglutide treatment increased the biliary concentration of cholesterol, phospholipids and bile acids and thereby decreased the cholesterol saturation index. The resistance to CGD conferred by liraglutide is likely a result of increased bile acid synthesis and efficient bile acid transport. The expression of a key bile acid synthetic enzyme, Cyp7a1, was significantly increased in liraglutide-treated mice. The increased expression of Cyp7a1 resulted from a relieved suppression signal of Fgf15 from the ileum. Mechanistically, liraglutide treatment altered bile acid composition and suppressed FXR activity in the ileum. Genetic ablation or pharmacological inhibition of FXR in the intestine protected mice against CGD. More importantly, intestinal FXR was required for liraglutide-mediated regulation of hepatic expression of Cyp7a1. CONCLUSION Liraglutide improved CGD by increasing bile acid secretion and decreasing cholesterol saturation index. Liraglutide attenuates the negative feedback inhibition of bile acids through inhibiting intestinal FXR activity. Our results suggest that liraglutide may represent a novel way for treating or preventing cholesterol gallstones in individuals with high risk of CGD.