Zijing Zhang1, Zuo Du2, Qinhui Liu3, Tong Wu1, Qin Tang1, Jinhang Zhang1, Cuiyuan Huang1, Ya Huang1, Rui Li1, Yanping Li4, Yingnan Zhao1, Guorong Zhang1, Jian Zhou1, Hui Huang1, ZhongZe Fang5, Jinhan He6. 1. Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China; Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China. 2. Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China. 3. Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China. 4. Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China. 5. Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, China. Electronic address: fangzhongze@tmu.edu.cn. 6. Laboratory of Clinical Pharmacy and Adverse Drug Reaction, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China; Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, China. Electronic address: jinhanhe@scu.edu.cn.
Abstract
BACKGROUND & AIMS: Cholesterol gallstone disease (CGD) is a common gastrointestinal disease. Liraglutide, an analogue 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.
BACKGROUND & AIMS:Cholesterol gallstone disease (CGD) is a common gastrointestinal disease. Liraglutide, an analogue 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.
Authors: Qian Zhuang; Jinnian Cheng; Jie Xia; Min Ning; Shan Wu; Shuang Shen; Yan Shi; Dan Huang; Zhixia Dong; Xinjian Wan Journal: Front Med (Lausanne) Date: 2022-04-04