Article

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

Ying-quan Wen1,2, Zi-yuan Zou2,3, Guan-guan Zhao2,4, Meng-jiao Zhang5, Yong-xin Zhang2,6, Gai-hong Wang7, Jing-jing Shi7, Yuan-yang Wang2,8, Ye-yu Song2,3, Hui-xia Wang7, Ru-ye Chen7, Dong-xuan Zheng7, Xiao-qun Duan9, Ya-meng Liu2, Frank J. Gonzalez10, Jian-gao Fan3, Cen Xie1,2,5,6
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
Correspondence to: Ya-meng Liu: yameng_liu@simm.ac.cn, Jian-gao Fan: fanjiangao@xinhuamed.com.cn, Cen Xie: xiecen@simm.ac.cn,
DOI: 10.1038/s41401-024-01329-1
Received: 15 January 2024
Accepted: 28 May 2024
Advance online: 11 July 2024

Abstract

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.
Keywords: MASLD/MASH; FXR; transcriptome; gut-liver axis; agonist

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