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

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

doi:10.1038/s41420-021-00707-6

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a prototypical metabolic disorder influenced by genetic and environmental factors
Herrero-Cervera et al [19] have investigated the effect of LIGHT deletion on the pathogenesis of NAFLD in mice and found that LIGHT deficiency attenuated hepatic inflammation owing to defective leukocyte infiltration in a high-fat diet (HFD) induced model
We report here that downregulation of transcriptional repressor HES5 leads to LIGHT upregulation and may contribute to hepatocyte apoptosis in the context of NAFLD

Summary

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is a prototypical metabolic disorder influenced by genetic and environmental factors. Herrero-Cervera et al [19] have investigated the effect of LIGHT deletion on the pathogenesis of NAFLD in mice and found that LIGHT deficiency attenuated hepatic inflammation owing to defective leukocyte infiltration in a high-fat diet (HFD) induced model. These intriguing findings notwithstanding, it remains unclear how LIGHT expression is regulated and whether LIGHT contributes to hepatocyte apoptosis in the course of NAFLD pathogenesis. We report here that downregulation of transcriptional repressor HES5 leads to LIGHT upregulation and may contribute to hepatocyte apoptosis in the context of NAFLD

RESULTS

Miao et al 2

DISCUSSION

METHODS