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 () and Shelly C. Lu ()
Additional contact information
Bing Yang: Cedars-Sinai Medical Center, LA
Liqing Lu: Cedars-Sinai Medical Center, LA
Ting Xiong: Cedars-Sinai Medical Center, LA
Wei Fan: Cedars-Sinai Medical Center, LA
Jiaohong Wang: Cedars-Sinai Medical Center, LA
Lucía Barbier-Torres: Cedars-Sinai Medical Center, LA
Jyoti Chhimwal: Cedars-Sinai Medical Center, LA
Sonal Sinha: Cedars-Sinai Medical Center, LA
Takashi Tsuchiya: Cedars-Sinai Medical Center, LA
Nirmala Mavila: Cedars-Sinai Medical Center, LA
Maria Lauda Tomasi: Cedars-Sinai Medical Center, LA
DuoYao Cao: CSMC LA
Jing Zhang: Cedars-Sinai Medical Center, LA
Hui Peng: Cedars-Sinai Medical Center, LA
José M. Mato: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia
Ting Liu: Central South University
Xi Yang: The First Affiliated Hospital of Guangxi Medical University
Vladimir V. Kalinichenko: University of Arizona College of Medicine
Komal Ramani: Cedars-Sinai Medical Center, LA
Jenny Han: Cedars-Sinai Medical Center, LA
Ekihiro Seki: Cedars-Sinai Medical Center, LA
Heping Yang: Cedars-Sinai Medical Center, LA
Shelly C. Lu: Cedars-Sinai Medical Center, LA

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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 Foxm1Hep−/−, hepatocytes from Foxm1HSC−/−, and HSCs and hepatocytes from Foxm1KC−/− 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.

Date: 2024
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DOI: 10.1038/s41467-024-52527-8

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