Fexaramine improves non-alcoholic fatty liver disease in mice by stimulating intestinal FXR
10.16438/j.0513-4870.2023-0299
- VernacularTitle:Fexaramine通过激动肠道FXR改善小鼠非酒精性脂肪性肝病的研究
- Author:
Lu-yao HUANG
1
;
Qiong-wen XUE
1
;
Yi-xuan LUO
1
;
Zi-xuan WANG
1
;
Jia-rui JIANG
1
;
Shu-yang XU
1
;
Li YANG
1
;
Zheng-tao WANG
1
;
Li-li DING
1
Author Information
1. The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
- Publication Type:Research Article
- Keywords:
fexaramine;
non-alcoholic fatty liver disease;
farnesoid X receptor;
bile acid;
lipid metabolism
- From:
Acta Pharmaceutica Sinica
2023;58(11):3330-3338
- CountryChina
- Language:Chinese
-
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is considered to be a manifestation of metabolic syndrome and has become one of the chronic diseases that endanger health around the world. There is still a lack of effective therapeutic drugs in clinical practice. Farnesoid X receptor (FXR) has been a popular target for NAFLD research in recent years. Fexaramine (Fex) is a potent and selective agonist of FXR, and its mechanism of action to improve NAFLD is unclear. Therefore, in this study, a mouse model of NAFLD was constructed using a high-fat, high-cholesterol diet and treated with Fex orally for 6 weeks. We evaluated the ameliorative effect of Fex on disorders of glucolipid metabolism in NAFLD mice, and preliminarily explored its potential mechanism of action. The animal experiments were approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine (approval number: PZSHUTCM210913011). In this study, it was found that 100 mg·kg-1 Fex significantly inhibited body weight gain, alleviated insulin resistance, improved liver injury and lipid accumulation in NAFLD mice. The effect of Fex on the expression of hepatic intestinal FXR and its target genes in NAFLD mice was further examined. Analysis of serum and hepatic bile acid profiles and expression related to hepatic lipid metabolism. It was found that Fex could stimulate intestinal FXR, promote fibroblast growth factor 15 (FGF15) secretion, inhibit the expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, regulate bile acid synthesis by negative feedback, and improve the disorder of bile acid metabolism. At the same time, Fex reduces liver lipid synthesis and absorption, increases fatty acid oxidation, thus improving liver lipid metabolism. This study shows that Fex can improve NAFLD by activating intestinal FXR-FGF15 signal pathway and regulating liver lipid metabolism.
