Glycine-beta-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice
文献类型：期刊论文
| 作者 | Jiang, Jie6,7; Ma, Yuandi5,6; Liu, Yameng6; Lu, Dasheng4; Gao, Xiaoxia4; Krausz, Kristopher W.4; Desai, Dhimant3; Amin, Shantu G.3; Patterson, Andrew D.1,2; Gonzalez, Frank J.4 |
| 刊名 | HEPATOLOGY COMMUNICATIONS
 |
| 出版日期 | 2022-10-05 |
| 页码 | 16 |
| DOI | 10.1002/hep4.2099 |
| 通讯作者 | Gonzalez, Frank J.(gonzalef@mail.nih.gov) ; Xie, Cen(cenxie@simm.ac.cn) |
| 英文摘要 | Nonalcoholic steatohepatitis (NASH) is a rapidly developing pathology around the world, with limited treatment options available. Some farnesoid X receptor (FXR) agonists have been applied in clinical trials for NASH, but side effects such as pruritus and low-density lipoprotein elevation have been reported. Intestinal FXR is recognized as a promising therapeutic target for metabolic diseases. Glycine-beta-muricholic acid (Gly-MCA) is an intestine-specific FXR antagonist previously shown to have favorable metabolic effects on obesity and insulin resistance. Herein, we identify a role for Gly-MCA in the pathogenesis of NASH, and explore the underlying molecular mechanism. Gly-MCA improved lipid accumulation, inflammatory response, and collagen deposition in two different NASH models. Mechanistically, Gly-MCA decreased intestine-derived ceramides by suppressing ceramide synthesis-related genes via decreasing intestinal FXR signaling, leading to lower liver endoplasmic reticulum (ER) stress and proinflammatory cytokine production. The role of bile acid metabolism and adiposity was excluded in the suppression of NASH by Gly-MCA, and a correlation was found between intestine-derived ceramides and NASH severity. This study revealed that Gly-MCA, an intestine-specific FXR antagonist, has beneficial effects on NASH by reducing ceramide levels circulating to liver via lowering intestinal FXR signaling, and ceramide production, followed by decreased liver ER stress and NASH progression. Intestinal FXR is a promising drug target and Gly-MCA a novel agent for the prevention and treatment of NASH. |
| WOS关键词 | ENDOPLASMIC-RETICULUM STRESS ; INSULIN-RESISTANCE ; LIVER ; STEATOHEPATITIS ; SPHINGOLIPIDS ; PATHOGENESIS |
| 资助项目 | National Natural Science Foundation of China[91957116] ; National Key Research and Development Program of China[2021YFA1301200] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Rising-Star Program[20QA1411200] ; National Institutes of Health, Intramural Research Program ; National Institutes of Health, National Institute of Diabetes and Digestive Diseases[U01DK119702] |
| WOS研究方向 | Gastroenterology & Hepatology |
| 语种 | 英语 |
| WOS记录号 | WOS:000863821400001 |
| 出版者 | JOHN WILEY & SONS LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/302658]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Gonzalez, Frank J.; Xie, Cen |
| 作者单位 | 1.Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA 2.Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA 3.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA 4.Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA USA 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jiang, Jie,Ma, Yuandi,Liu, Yameng,et al. Glycine-beta-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice[J]. HEPATOLOGY COMMUNICATIONS,2022:16. |
| APA | Jiang, Jie.,Ma, Yuandi.,Liu, Yameng.,Lu, Dasheng.,Gao, Xiaoxia.,...&Xie, Cen.(2022).Glycine-beta-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice.HEPATOLOGY COMMUNICATIONS,16. |
| MLA | Jiang, Jie,et al."Glycine-beta-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice".HEPATOLOGY COMMUNICATIONS (2022):16. |
入库方式： OAI收割
来源：上海药物研究所
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