BRG1 Links TLR4 Trans-Activation to LPS-Induced SREBP1a Expression and Liver Injury.

Wenhui Dong,Yuwen Zhu,Ziyu Zhang,Yong Xu,Xiangshan Fan,Yangxi Zhang,Zhiwen Fan

doi:10.3389/fcell.2021.617073

Abstract

Multiple organ failure is one of the most severe consequences in patients with septic shock. Liver injury is frequently observed during this pathophysiological process. In the present study we investigated the contribution of Brahma related gene 1 (BRG1), a chromatin remodeling protein, to septic shock induced liver injury. When wild type (WT) and liver conditional BRG1 knockout (LKO) mice were injected with lipopolysaccharide (LPS), liver injury was appreciably attenuated in the LKO mice compared to the WT mice as evidenced by plasma ALT/AST levels, hepatic inflammation and apoptosis. Of interest, there was a down-regulation of sterol response element binding protein 1a (SREBP1a), known to promote liver injury, in the LKO livers compared to the WT livers. BRG1 did not directly bind to the SREBP1a promoter. Instead, BRG1 was recruited to the toll-like receptor 4 (TLR4) promoter and activated TLR4 transcription. Ectopic TLR4 restored SREBP1a expression in BRG1-null hepatocytes. Congruently, adenovirus carrying TLR4 or SREBP1a expression vector normalized liver injury in BRG1 LKO mice injected with LPS. Finally, a positive correlation between BRG1 and TLR4 expression was detected in human liver biopsy specimens. In conclusion, our data demonstrate that a BRG1-TLR4-SREBP1a axis that mediates LPS-induced liver injury in mice.

Highlights

Septic shock, or septicemia, is a common pathophysiological process taking place in a wide range of occasions including infection, trauma, diabetes, and cirrhosis (Hotchkiss et al, 2016)
Quantitative PCR results showed that the expression levels of several pro-inflammatory mediators, including Il-1b, Il-6, and Tnf-a, as well as several pro-apoptotic molecules, including Bax, Bim, and Noxa, were down-regulated in the liver conditional BRG1 knockout (LKO) livers compared to the wild type (WT) livers (Figure 1E)
We probed the relationship between Brahma related gene 1 (BRG1) and toll-like receptor 4 (TLR4) expression in human liver biopsy specimens

Summary

Introduction

Septicemia, is a common pathophysiological process taking place in a wide range of occasions including infection, trauma, diabetes, and cirrhosis (Hotchkiss et al, 2016). Liver dysfunction is common in patients with septic shock, which can be generally characterized as elevated plasma levels of alanine transaminase, alkaline phosphatase, and bilirubin (jaundice). Altered inflammatory response is considered another critical contributing factor to sepsis-induced liver injury. It has been well-documented that enteric microbes and their components [e.g., lipopolysaccharide (LPS)] trans-located to the liver due to the disruption of the intestinal barrier function, combined with hepatic ischemia, illicit hepatic inflammation during sepsis (Yan and Li, 2014). Hepatocytespecific deletion or pharmaceutical inhibition of toll-like receptor 4 (TLR4), a master regulator of cellular inflammation to which LPS binds, attenuates liver injury following sepsis (Deng et al, 2013; Engelmann et al, 2020). How TLR4 expression is regulated in this process is not well understood

Methods

Results

Conclusion