The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation

Guangyong Sun; Yunxiong Wei; Jingjing Zhu; Shimeng Zheng; Zihan Zhang; Dong Zhang

doi:10.1016/j.bbrc.2023.10.014

The transcription factor T-bet promotes the pathogenesis of nonalcoholic fatty liver disease by upregulating intrahepatic inflammation

Biochem Biophys Res Commun. 2023 Nov 19:682:266-273. doi: 10.1016/j.bbrc.2023.10.014. Epub 2023 Oct 4.

Authors

Guangyong Sun¹, Yunxiong Wei², Jingjing Zhu², Shimeng Zheng², Zihan Zhang¹, Dong Zhang³

Affiliations

¹ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, 100069, China.
² Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
³ Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, 100069, China; Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. Electronic address: zhangd@ccmu.edu.cn.

PMID: 37832383
DOI: 10.1016/j.bbrc.2023.10.014

Abstract

Objective: To investigate the effect of the transcription factor T-bet on the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the regulation of the intrahepatic immune microenvironment.

Methods: Wild-type and T-bet knockout NASH mouse models were constructed. The effect of T-bet knockout on the pathogenesis of NAFLD was observed by histochemical staining. The expression of T-bet in immune cells in the liver and the effect of T-bet knockout on the proportion and function of immune cell subsets in the liver were determined by flow analysis.

Results: Flow cytometry results indicated that T-bet expression was increased in immune cells, especially NKT cells, in the livers of NAFLD mice. Knocking out the transcription factor T-bet reduced intrahepatic inflammation, reduced lipid accumulation, and ameliorated the pathogenesis of NAFLD. Based on the analysis of immune cell subsets, knocking out the transcription factor T-bet decreased the proportion, survival, and degree of activation of NK, NKT, and CD8 T cells in NAFLD liver; additionally, it decreased the secretion of IFN-γ by T cells and NKT cells but had no effect on the proportion of Th17 cells and Treg cells. Knocking out the transcription factor T-bet also reduced the proportion of proinflammatory myeloid-derived macrophages (MoMFs) in NAFLD liver, mainly the proportion of proinflammatory Ly6C^high MoMFs. Furthermore, knocking out the transcription factor T-bet had no significant effect on the secretion of TNF-α from MoMFs but significantly reduced the expression of MHC class II molecules. Further analysis showed that the transcription factor T-bet may directly affect the expression of MHC class II molecules H2-AB1 and H2-Dmb1 through transcriptional regulation.

Conclusions: Knocking out the transcription factor T-bet reduced the proinflammatory effect of innate immune cells (MoMFs, NK cells, and NKT cells) and T lymphocytes in NAFLD liver, thereby reducing intrahepatic inflammation and delaying the pathogenesis of NAFLD.

Keywords: IFN-γ; Inflammation; Nonalcoholic fatty liver disease; T-bet.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Histocompatibility Antigens Class II / metabolism
Inflammation / pathology
Liver / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease* / metabolism
Transcription Factors / metabolism

Substances

Histocompatibility Antigens Class II
Transcription Factors
T-box transcription factor TBX21