Bdh1 overexpression ameliorates hepatic injury by activation of Nrf2 in a MAFLD mouse model

In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease “MAFLD” as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an impor...

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Published inCell death discovery Vol. 8; no. 1; p. 49
Main Authors Xu, Bu-tuo, Teng, Fang-yuan, Wu, Qi, Wan, Sheng-rong, Li, Xin-yue, Tan, Xiao-zhen, Xu, Yong, Jiang, Zong-zhe
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 03.02.2022
Springer Nature B.V
Nature Publishing Group
Subjects
631/80/82/23
692/699/1503/1607/2750
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Fatty liver
Fibrosis
Inflammation
Life Sciences
Liver diseases
Metabolic flux
Metabolism
Palmitic acid
Stem Cells
Therapeutic targets
Transgenic mice
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Summary:In 2020, a group of experts officially suggested metabolic dysfunction associated with fatty liver disease “MAFLD” as a more appropriate overarching term than NAFLD, indicating the key role of metabolism in fatty liver disease. Bdh1, as the rate-limiting enzyme of ketone metabolism, acts as an important metabolic regulator in liver. However, the role of Bdh1 in MAFLD is unclear. In this study, we used the transgenic db/db mice as a MAFLD mouse model and observed the downregulated expression of Bdh1 in fatty liver. In addition, expression of Bdh1 was also reduced by palmitic acid (PA) treatment in LO2 cells. Bdh1 knockdown led to ROS overproduction and ROS-induced inflammation and apoptosis in LO2 cells, while Bdh1 overexpression protected LO2 cells from lipotoxicity by inhibiting ROS overproduction. Mechanistically, Bdh1-mediated βOHB metabolism inhibits ROS overproduction by activation of Nrf2 through enhancement of metabolic flux composed of βOHB-AcAc-succinate-fumarate. Notably, adeno-associated virus (AAV)-mediated Bdh1 overexpression successfully reversed the hepatic function indexes, fibrosis, inflammation, and apoptosis in fatty livers from db/db mice. In conclusion, our study revealed a Bdh1-mediated molecular mechanism in pathogenesis of metabolic dysfunction related liver disease and identified Bdh1 as a novel potential therapeutic target for MAFLD.
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ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-022-00840-w