A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters
文献类型:期刊论文
作者 | Wang, Ying1,2; Zhu, Yao1,2; Niu, Junxing1,2; Deng, Qiangqiang1,2; Guo, Shimeng1,2,3; Jiang, Haowen1,2,3; Peng, Zhaoliang1,2; Xue, Yaru1,2; Peng, Huige1,2; Xuan, Lijiang1,2 |
刊名 | TOXICOLOGY AND APPLIED PHARMACOLOGY |
出版日期 | 2020-10-01 |
卷号 | 404页码:14 |
ISSN号 | 0041-008X |
关键词 | Bile acid analog NASH TGR5 Cd36 AMPK alpha |
DOI | 10.1016/j.taap.2020.115169 |
通讯作者 | Xuan, Lijiang(ljxuan@simm.ac.cn) ; Pan, Guoyu(gypan@simm.ac.cn) |
英文摘要 | Being endocrine signaling molecules that regulate lipid metabolism and affect energy balance, bile acids are potential drug candidates for non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) could improve NASH accompanied by significant side effects. Therefore, it is worthwhile to develop safer and more effective bile acid analogs. In this study, a new bile acid analog A17 was synthesized and its potential anti-NASH effects were assessed in vitro and in vivo. The impact of A17 on steatosis was investigated in the rat primary hepatocytes challenged with oleic acid. It was found that A17 alleviated lipid accumulation by reducing fatty acid (FA) uptake and promoting FA oxidation. The reduction of FA uptake came from inhibiting fatty acid translocase (Cd36) expression. The promotion of FA oxidation came from stimulating the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha (AMPK alpha). In addition, A17 reduced lipopolysaccharide-induced inflammation in Raw264.7 cells by activating Takeda G protein-coupled receptor 5 (TGR5). In in vivo study, male Golden Syrian hamsters were fed with high fat (HF) diet and then treated with 50 mg/kg/d A17 for 6 weeks. A17 lowered the lipid profiles and liver enzyme levels in serum and improved liver pathological conditions with less side effects compared with OCA. Further studies confirmed that the molecular mechanisms of A17 in vivo were similar to those in vitro. In conclusion, a novel bile acid analog A17 was identified to ameliorate NASH in HF-fed hamsters. The potential mechanisms could be contributed to reducing FA uptake, stimulating FA oxidation and relieving inflammation. |
WOS关键词 | LIVER-DISEASE ; NATURAL-HISTORY ; TGR5 ; ACTIVATION ; PATHWAY ; EPIDEMIOLOGY ; PATHOGENESIS ; INFLAMMATION ; DERIVATIVES ; RECEPTOR |
资助项目 | Strategic Priority Research Program of the Chinese Academy of Sciences[XDA16020205] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040335] ; National Natural Science Foundation of China[81872927] ; National Natural Science Foundation of China[81773863] ; International Partnership Program of Chinese Academy of Sciences[153631KYSB20160004] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the hinese Academy of Sciences[CASIMM0120184005] ; Youth Innovation Promotion Association ; National Science and Technology Major Project[2019ZX09201004-003041] ; National Science and Technology Major Project[2019ZX09201004-003-042] ; China Postdoctoral Science Foundation[2019M651623] |
WOS研究方向 | Pharmacology & Pharmacy ; Toxicology |
语种 | 英语 |
出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
WOS记录号 | WOS:000566798000007 |
源URL | [http://119.78.100.183/handle/2S10ELR8/291099] |
专题 | 新药研究国家重点实验室 |
通讯作者 | Xuan, Lijiang; Pan, Guoyu |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Wang, Ying,Zhu, Yao,Niu, Junxing,et al. A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2020,404:14. |
APA | Wang, Ying.,Zhu, Yao.,Niu, Junxing.,Deng, Qiangqiang.,Guo, Shimeng.,...&Pan, Guoyu.(2020).A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters.TOXICOLOGY AND APPLIED PHARMACOLOGY,404,14. |
MLA | Wang, Ying,et al."A novel bile acid analog, A17, ameliorated non-alcoholic steatohepatitis in high-fat diet-fed hamsters".TOXICOLOGY AND APPLIED PHARMACOLOGY 404(2020):14. |
入库方式: OAI收割
来源:上海药物研究所
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