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

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

Nat Commun. 2024 Sep 27;15(1):8388. doi: 10.1038/s41467-024-52527-8.

Authors

Bing Yang^#^{1

2}, Liqing Lu^#^{1

3}, Ting Xiong^#^{1

4}, Wei Fan¹, Jiaohong Wang¹, Lucía Barbier-Torres¹, Jyoti Chhimwal¹, Sonal Sinha¹, Takashi Tsuchiya¹, Nirmala Mavila¹, Maria Lauda Tomasi¹, DuoYao Cao⁵, Jing Zhang^{1

6}, Hui Peng¹, José M Mato⁷, Ting Liu⁸, Xi Yang², Vladimir V Kalinichenko^{9

10}, Komal Ramani¹, Jenny Han^{1

11}, Ekihiro Seki¹, Heping Yang¹², Shelly C Lu¹³

Affiliations

¹ Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA, Los Angeles, CA, 90048, USA.
² 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, Nanning, Guangxi, 530021, China.
³ Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁴ Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan, 410015, China.
⁵ Department of Biomedical Sciences, CSMC LA, Los Angeles, CA, 90048, USA.
⁶ Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁷ CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology, Park of Bizkaia, 48120, Derio, Bizkaia, Spain.
⁸ Department of Gastroenterology, Xiangya Hospital, Key Laboratory of Cancer proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁹ Phoenix Children's Research Institute, Department of Child Health, University of Arizona College of Medicine, Phoenix, AZ, 85004, USA.
¹⁰ Division of Neonatology, Phoenix Children's Hospital, Phoenix, AZ, 85016, USA.
¹¹ Department of Society and Genetics, UCLA LA, Los Angeles, CA, 92620, USA.
¹² Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA, Los Angeles, CA, 90048, USA. Heping.yang@cshs.org.
¹³ Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, LA, Los Angeles, CA, 90048, USA. shelly.lu@cshs.org.

^# Contributed equally.

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.

MeSH terms

Animals
Bile Ducts / metabolism
Bile Ducts / pathology
Bile Ducts / surgery
Carbon Tetrachloride* / toxicity
Forkhead Box Protein M1* / genetics
Forkhead Box Protein M1* / metabolism
Hepatic Stellate Cells* / metabolism
Hepatocytes* / metabolism
Hepatocytes* / pathology
Humans
Inflammation / genetics
Inflammation / metabolism
Inflammation / pathology
Kupffer Cells* / metabolism
Liver / metabolism
Liver / pathology
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Male
Methionine Adenosyltransferase* / genetics
Methionine Adenosyltransferase* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic

Substances

Methionine Adenosyltransferase
Forkhead Box Protein M1
Foxm1 protein, mouse
Carbon Tetrachloride
Mat2a protein, mouse

Abstract

MeSH terms

Substances

Grants and funding