FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis  

作　　者：Ying-quan Wen Zi-yuan Zou Guan-guan Zhao Meng-jiao Zhang Yong-xin Zhang Gai-hong Wang Jing-jing Shi Yuan-yang Wang Ye-yu Song Hui-xia Wang Ru-ye Chen Dong-xuan Zheng Xiao-qun Duan Ya-meng Liu Frank J.Gonzalez Jian-gao Fan Cen Xie 

机构地区：[1]School of Pharmacy,Jiangxi Medical College,Nanchang University,Nanchang,330006,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [3]Department of Gastroenterology,Center for Fatty Liver,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai Key Lab of Pediatric Gastroenterology and Nutrition,Shanghai,200092,China [4]Xiangya Hospital,Central South University,Changsha,410013,China [5]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210029,China [6]University of the Chinese Academy of Sciences,Beijing,100049,China [7]Cascade Pharmaceuticals,Inc,Shanghai,201321,China [8]Department of Laboratory Medicine and Central Laboratory,Shanghai Tenth People’s Hospital,Tongji University,Shanghai,200072,China [9]Industrial Technology Research Institute of Pharmacy,Guilin Medical University,Guilin,541199,China [10]Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD,USA

出　　处：《Acta Pharmacologica Sinica》2024年第11期2313-2327,共15页中国药理学报（英文版）

基　　金：supported by the 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(82222071,91957116,82173873);and Project supported by Shanghai Municipal Science and Technology Major Project.

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.

关 键 词：MASLD/MASH FXR TRANSCRIPTOME gut-liver axis AGONIST 

分 类 号：R575.1[医药卫生—消化系统]