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

Autor: Wen YQ; School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China., Zou ZY; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; 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., Zhao GG; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; Xiangya Hospital, Central South University, Changsha, 410013, China., Zhang MJ; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China., Zhang YX; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of the Chinese Academy of Sciences, Beijing, 100049, China., Wang GH; Cascade Pharmaceuticals, Inc, Shanghai, 201321, China., Shi JJ; Cascade Pharmaceuticals, Inc, Shanghai, 201321, China., Wang YY; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China., Song YY; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; 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., Wang HX; Cascade Pharmaceuticals, Inc, Shanghai, 201321, China., Chen RY; Cascade Pharmaceuticals, Inc, Shanghai, 201321, China., Zheng DX; Cascade Pharmaceuticals, Inc, Shanghai, 201321, China., Duan XQ; Industrial Technology Research Institute of Pharmacy, Guilin Medical University, Guilin, 541199, China., Liu YM; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yameng_liu@simm.ac.cn., Gonzalez FJ; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Fan JG; 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. fanjiangao@xinhuamed.com.cn., Xie C; School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. xiecen@simm.ac.cn.; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xiecen@simm.ac.cn.; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China. xiecen@simm.ac.cn.; University of the Chinese Academy of Sciences, Beijing, 100049, China. xiecen@simm.ac.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Nov; Vol. 45 (11), pp. 2313-2327. Date of Electronic Publication: 2024 Jul 11.
DOI: 10.1038/s41401-024-01329-1
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz: