中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis

文献类型：期刊论文

作者Wen, Ying-quan10,11; Zou, Zi-yuan9,10; Zhao, Guan-guan8,10; Zhang, Meng-jiao7; Zhang, Yong-xin6,10; Wang, Gai-hong5; Shi, Jing-jing5; Wang, Yuan-yang1,4,10; Song, Ye-yu9,10; Wang, Hui-xia5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-07-11
页码15
关键词MASLD/MASH FXR transcriptome gut-liver axis agonist
ISSN号1671-4083
DOI10.1038/s41401-024-01329-1
通讯作者Liu, Ya-meng(yameng_liu@simm.ac.cn) ; Fan, Jian-gao(fanjiangao@xinhuamed.com.cn) ; Xie, Cen(xiecen@simm.ac.cn)
英文摘要The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.
WOS关键词FATTY LIVER-DISEASE ; NONALCOHOLIC STEATOHEPATITIS ; NUCLEAR RECEPTOR ; BILE-ACID ; NASH ; FIBROSIS ; EPIDEMIOLOGY
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDB39020600] ; National Key Research and Development Program of China[2021YFA1301200] ; National Natural Science Foundation of China[82222071] ; National Natural Science Foundation of China[91957116] ; National Natural Science Foundation of China[82173873] ; Shanghai Municipal Science and Technology Major Project
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001269069000002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/312368]  
专题新药研究国家重点实验室
通讯作者Liu, Ya-meng; Fan, Jian-gao; Xie, Cen
作者单位1.Tongji Univ, Dept Lab Med, Shanghai 200072, Peoples R China
2.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
3.Guilin Med Univ, Ind Technol Res Inst Pharm, Guilin 541199, Peoples R China
4.Tongji Univ, Shanghai Peoples Hosp 10, Cent Lab, Shanghai 200072, Peoples R China
5.Cascade Pharmaceut Inc, Shanghai 201321, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210029, Peoples R China
8.Cent South Univ, Xiangya Hosp, Changsha 410013, Peoples R China
9.Shanghai Jiao Tong Univ, Ctr Fatty Liver, Shanghai Key Lab Pediat Gastroenterol & Nutr, Dept Gastroenterol,Xinhua Hosp,Sch Med, Shanghai 200092, Peoples R China
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Wen, Ying-quan,Zou, Zi-yuan,Zhao, Guan-guan,et al. FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis[J]. ACTA PHARMACOLOGICA SINICA,2024:15.
APA Wen, Ying-quan.,Zou, Zi-yuan.,Zhao, Guan-guan.,Zhang, Meng-jiao.,Zhang, Yong-xin.,...&Xie, Cen.(2024).FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.ACTA PHARMACOLOGICA SINICA,15.
MLA Wen, Ying-quan,et al."FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis".ACTA PHARMACOLOGICA SINICA (2024):15.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。