Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production.

Yong Xu,Tinghui Shao,Yan Guo,Yujia Xue,Xiulian Miao,Fangqiao Lv,Yutong Wang

doi:10.3389/fcell.2021.745985

Abstract

Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte. Here we report that BRG1 deletion led to simultaneous down-regulation in expression and phosphorylation of tank binding kinase 1 (TBK1) in vivo and in vitro. On the one hand, BRG1 interacted with AP-1 to bind to the TBK1 promoter and directly activated TBK1 transcription in hepatocytes. On the other hand, BRG1 interacted with Sp1 to activate the transcription of c-SRC, a tyrosine kinase essential for TBK1 phosphorylation. Over-expression of c-SRC and TBK1 corrected the deficiency in ROS production in BRG1-null hepatocytes whereas depletion of TBK1 or c-SRC attenuated ROS production. In conclusion, our data suggest that dual regulation of TBK1 activity, at the transcription level and the post-transcriptional level, by BRG1 may constitute an important mechanism underlying excessive ROS production in hepatocytes.

Highlights

Non-alcoholic fatty liver disease (NAFLD) represents a continuum of pathologies ranging from simple steatosis, to steatohepatitis, to cirrhosis (Michelotti et al, 2013)
Primary hepatocytes were isolated from wild type (WT) and BRG1LKO mice and treated with palmitate (0.4 mM) for 12 h as previously described (Hong et al, 2020; Dong et al, 2021)
Western blotting showed that tank binding kinase 1 (TBK1) protein levels were down-regulated in the high-fat high carbohydrate (HFHC)-fed LKO livers compared to the HFHC-fed WT livers (Figure 1C)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) represents a continuum of pathologies ranging from simple steatosis, to steatohepatitis, to cirrhosis (Michelotti et al, 2013). Due to changes in life styles and dietary choices, recent decades have seen drastically increased prevalence of NAFLD, which is projected to become the most important underlying cause for hepatocellular carcinoma and liver transplantation (Anstee et al, 2019). Despite advances in the understanding of its pathogenesis, therapeutic solutions for NAFLD are limited. The mechanisms that contribute to NAFLD pathogenesis are complex, which include aberrant systemic and hepatic metabolism, lowmagnitude sterile inflammation (i.e., meta-inflammation), and oxidative stress owing to excessive production and/or ineffective removal of reactive oxygen species (ROS) (Wesolowski et al, 2017).

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Conclusion