The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis

Bing Yang; Liqing Lu; Ting Xiong; Wei Fan; Jiaohong Wang; Lucía Barbier-Torres; Jyoti Chhimwal; Sonal Sinha; Takashi Tsuchiya; Nirmala Mavila; Maria Lauda Tomasi; DuoYao Cao; Jing Zhang; Hui Peng; José M. Mato; Ting Liu; Xi Yang; Vladimir V. Kalinichenko; Komal Ramani; Jenny Han; Ekihiro Seki; Heping Yang; Shelly C. Lu

doi:10.1038/s41467-024-52527-8

Nature Communications (Sep 2024)

The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis

Bing Yang,
Liqing Lu,
Ting Xiong,
Wei Fan,
Jiaohong Wang,
Lucía Barbier-Torres,
Jyoti Chhimwal,
Sonal Sinha,
Takashi Tsuchiya,
Nirmala Mavila,
Maria Lauda Tomasi,
DuoYao Cao,
Jing Zhang,
Hui Peng,
José M. Mato,
Ting Liu,
Xi Yang,
Vladimir V. Kalinichenko,
Komal Ramani,
Jenny Han,
Ekihiro Seki,
Heping Yang,
Shelly C. Lu

Affiliations

Bing Yang: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Liqing Lu: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Ting Xiong: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Wei Fan: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Jiaohong Wang: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Lucía Barbier-Torres: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Jyoti Chhimwal: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Sonal Sinha: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Takashi Tsuchiya: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Nirmala Mavila: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Maria Lauda Tomasi: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
DuoYao Cao: Department of Biomedical Sciences, CSMC LA
Jing Zhang: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Hui Peng: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
José M. Mato: CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia
Ting Liu: Department of Gastroenterology, Xiangya Hospital, Key Laboratory of Cancer proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University
Xi Yang: Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University
Vladimir V. Kalinichenko: Phoenix Children’s Research Institute, Department of Child Health, University of Arizona College of Medicine
Komal Ramani: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Jenny Han: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Ekihiro Seki: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Heping Yang: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA
Shelly C. Lu: Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA

DOI: https://doi.org/10.1038/s41467-024-52527-8
Journal volume & issue: Vol. 15, no. 1
pp. 1 – 20

Abstract

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Abstract Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice. We found FOXM1/MAT2A/2B are upregulated after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment in hepatocytes, HSCs and Kupffer cells (KCs). FDI-6, a FOXM1 inhibitor, attenuates the development and reverses the progression of CCl4-induced fibrosis while lowering the expression of FOXM1/MAT2A/2B, which exert reciprocal positive regulation on each other transcriptionally. Knocking down any of them lowers HSCs and KCs activation. Deletion of FOXM1 in hepatocytes, HSCs, and KCs protects from BDL-mediated inflammation and fibrosis comparably. Interestingly, HSCs from Foxm1 Hep−/−, hepatocytes from Foxm1 HSC−/−, and HSCs and hepatocytes from Foxm1 KC−/− have lower FOXM1/MAT2A/2B after BDL. This may be partly due to transfer of extracellular vesicles between different cell types. Altogether, FOXM1/MAT2A/MAT2B axis drives liver inflammation and fibrosis.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

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