The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis
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 (CCl<sub>4</sub>) treatment in hepatocytes, HSCs and Kupffer cells (KCs). FDI-6, a FOXM1 inhibitor, attenuates the development and reverses the progression of CCl<sub>4</sub>-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<sup>Hep-/-</sup>, hepatocytes from Foxm1<sup>HSC-/-</sup>, and HSCs and hepatocytes from Foxm1<sup>KC-/-</sup> 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.
Authors
- Vladimir V. Kalinichenko (ORCID: https://orcid.org/0000-0003-3438-2660)
- Sonal Sinha
- Lucía Barbier‐Torres (ORCID: https://orcid.org/0000-0002-7675-2888)
- José María Mato (ORCID: https://orcid.org/0000-0003-1264-3153)
- Shelly Chi-Loo Lu (ORCID: https://orcid.org/0000-0003-2128-5407)
- Bing Yang (ORCID: https://orcid.org/0000-0003-1860-0082)
- Komal Ramani (ORCID: https://orcid.org/0000-0002-2387-4603)
- Jiaohong Wang
- Ekihiro Seki (ORCID: https://orcid.org/0000-0002-9472-6085)
- Wei Fan (ORCID: https://orcid.org/0000-0001-6462-7425)
- Maria Lauda Tomasi (ORCID: https://orcid.org/0000-0001-8156-9052)
- Nirmala Mavila (ORCID: https://orcid.org/0000-0002-5608-3349)
- Jyoti Chhimwal (ORCID: https://orcid.org/0000-0002-6155-7721)
- Duo‐Yao Cao (ORCID: https://orcid.org/0000-0002-0455-4655)
- Ting Liu (ORCID: https://orcid.org/0000-0001-8178-6532)
- Ting Xiong (ORCID: https://orcid.org/0009-0000-7404-4880)
- Heping Yang (ORCID: https://orcid.org/0000-0003-1030-6495)
- Hui Peng (ORCID: https://orcid.org/0000-0002-4379-8097)
- Liqing Lu
- Takashi Tsuchiya (ORCID: https://orcid.org/0000-0002-3134-0986)
- Jenny Han
- Jing Zhang (ORCID: https://orcid.org/0009-0001-5370-0014)
- Xi Yang (ORCID: https://orcid.org/0000-0001-9647-9316)
Institutions
- Cedars-Sinai Medical Center (US)
- Central South University (CN)
- Guangxi Medical University (CN)
- Genetics Society of America (US)
- Los Angeles Medical Center (US)
- Hunan Cancer Hospital (CN)
- Phoenix Children's Hospital (US)
- First Affiliated Hospital of GuangXi Medical University (CN)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES)
- Xiangya Hospital Central South University (CN)
- Tongji Hospital (CN)
- Third Hospital of Changsha (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52527-8
- Citations
- 8
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- National Natural Science Foundation of China
- National Institutes of Health