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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: Transcriptomics profiling of livers in humans identifies core MASH transcriptional network.
Fig. 2: Transcriptomics profiling of livers in mice identifies core MASH transcriptional network.
Fig. 3: Treatment with FXR agonists alleviates MASH-associated phenotypes.
Fig. 4: FXR activation reverses the dysregulated core MASH transcriptional network.
Fig. 5: Machine learning predicts patients’ response to treatment of FXR agonists.
Fig. 6: Activation of FXR reduces molecular signatures of inflammation and fibrosis.
Fig. 7: Activation of intestinal FXR mitigates MASH through the gut-liver axis.

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Data availability

The bioProject accession for the hepatic transcriptomic data (Fxrf/f, Fxr△IE, Fxrf/f + OCA, and Fxr△IE + OCA mice) and intestinal transcriptomic data (Fxrf/f + OCA and Fxr△Hep + OCA mice) reported in this paper is PRJNA992640. The bioProject accession for the hepatic and intestinal transcriptomic data (FXR agonists treated mice) reported in this paper is PRJNA1030080.

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Acknowledgements

We thank Kang-long Wang, Peng-xiang Mu, and Cui-na Li for their help with animal dissection and sample collection. This study was 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.

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Author notes

  1. These authors contributed equally: Ying-quan Wen, Zi-yuan Zou, Guan-guan Zhao

Authors and Affiliations

  1. School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China

    Ying-quan Wen & Cen Xie

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ying-quan Wen, Zi-yuan Zou, Guan-guan Zhao, Yong-xin Zhang, Yuan-yang Wang, Ye-yu Song, Ya-meng Liu & Cen Xie

  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

    Zi-yuan Zou, Ye-yu Song & Jian-gao Fan

  4. Xiangya Hospital, Central South University, Changsha, 410013, China

    Guan-guan Zhao

  5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China

    Meng-jiao Zhang & Cen Xie

  6. University of the Chinese Academy of Sciences, Beijing, 100049, China

    Yong-xin Zhang & Cen Xie

  7. Cascade Pharmaceuticals, Inc, Shanghai, 201321, China

    Gai-hong Wang, Jing-jing Shi, Hui-xia Wang, Ru-ye Chen & Dong-xuan Zheng

  8. Department of Laboratory Medicine and Central Laboratory, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China

    Yuan-yang Wang

  9. Industrial Technology Research Institute of Pharmacy, Guilin Medical University, Guilin, 541199, China

    Xiao-qun Duan

  10. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Frank J. Gonzalez

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Contributions

YQW, GGZ, MJZ, YXZ, GHW, YYS, JJS, HXW, RYC, DXZ, and XQD performed the experiments. YQW and ZYZ analyzed the RNA-seq data. MJZ helped with luciferase reporter gene experiment. YQW, GGZ, ZYZ, YYW, and CX were responsible for the study concept and design. YQW and CX wrote the manuscript. CX, YML, FJG, and JGF supervised the study.

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Correspondence to Ya-meng Liu, Jian-gao Fan or Cen Xie.

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Wen, Yq., Zou, Zy., Zhao, Gg. et al. FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01329-1

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