HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes

Xiulian Miao; Yan Guo; Sheng Zeng; Xingyu Liu; Xiao Teng; Luyang Li; Wenxuan Hong

doi:10.1038/s41420-021-00707-6

HES5-mediated repression of LIGHT transcription may contribute to apoptosis in hepatocytes

Cell Death Discov. 2021 Oct 23;7(1):308. doi: 10.1038/s41420-021-00707-6.

Authors

Xiulian Miao^#¹, Yan Guo^#¹, Sheng Zeng^#², Xingyu Liu¹, Xiao Teng¹, Luyang Li³, Wenxuan Hong^{4

5}

Affiliations

¹ College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China.
² Stem Cell Center, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
³ Department of Oral Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China. liluyang1992@126.com.
⁴ College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China. 18111510041@fudan.edu.cn.
⁵ Institute of Biomedical Sciences, Fudan University, Shanghai, China. 18111510041@fudan.edu.cn.

^# Contributed equally.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is prototypical form of metabolic syndrome and has become a global pandemic. Hepatocytes undergo apoptosis in the pathogenesis of NAFLD. We report that the lymphokine LIGHT/TNFSF14 was upregulated in the murine NAFLD livers and in hepatocytes treated with free fatty acids (palmitate, PA). LIGHT knockdown or neutralization attenuated PA-induced apoptosis of hepatocytes. Similarly, knockdown or blockade of LTβR, the receptor for LIGHT, ameliorated apoptosis in hepatocytes exposed to PA. Ingenuity pathway analysis (IPA) revealed several Notch-related transcription factors as upstream regulators of LIGHT, of which HES5 expression was downregulated paralleling LIGHT induction in the pathogenesis of NAFLD. HES5 knockdown enhanced whereas HES5 over-expression weakened LIGHT induction in hepatocytes. HES5 was found to directly bind to the LIGHT promoter and repress LIGHT transcription. Mechanistically, HES5 interacted with SIRT1 to deacetylate histone H3/H4 on the LIGHT promoter to repress LIGHT transcription. SIRT1 knockdown or inhibition offset the effect of HES5 over-expression on LIGHT transcription and hepatocyte apoptosis. In conclusion, our data unveil a novel mechanism that might contribute to excessive apoptosis in hepatocyte exposed to free fatty acids.