The Chromatin Remodeling Protein BRG1 Regulates SREBP Maturation by Activating SCAP Transcription in Hepatocytes.

Ming Kong,Zhiwen Fan,Yuwen Zhu,Jing Shao,Yong Xu

doi:10.3389/fcell.2021.622866

Abstract

Sterol response element binding protein (SREBP) is a master regulator of cellular lipogenesis. One key step in the regulation of SREBP activity is its sequential cleavage and trans-location by several different proteinases including SREBP cleavage activating protein (SCAP). We have previously reported that Brahma related gene 1 (BRG1) directly interacts with SREBP1c and SREBP2 to activate pro-lipogenic transcription in hepatocytes. We report here that BRG1 deficiency resulted in reduced processing and nuclear accumulation of SREBP in the murine livers in two different models of non-alcoholic steatohepatitis (NASH). Exposure of hepatocytes to lipopolysaccharide (LPS) and palmitate (PA) promoted SREBP accumulation in the nucleus whereas BRG1 knockdown or inhibition blocked SREBP maturation. Further analysis revealed that BRG1 played an essential role in the regulation of SCAP expression. Mechanistically, BRG1 interacted with Sp1 and directly bound to the SCAP promoter to activate SCAP transcription. Forced expression of exogenous SCAP partially rescued the deficiency in the expression of SREBP target genes in BRG1-null hepatocytes. In conclusion, our data uncover a novel mechanism by which BRG1 contributes to SREBP-dependent lipid metabolism.

Highlights

Lipid is a major biological macromolecule that plays diverse roles in orchestrating differentiation, proliferation, migration, communication, survival, and death of mammalian cells (Glatz, 2011; Patil et al, 2019; Nechipurenko, 2020; Xie et al, 2020)
In the first model in which the mice were fed a high-fat diet (HFD) for 16 weeks, it was observed that nuclear SREBP1/2 levels were appreciably increased in the livers of the HFD-fed mice compared to the control diet-fed mice; up-regulation of nuclear SREBP1/2 by HFD feeding was more modest in the liver conditional BRG1 knockout (LKO) livers than in the WT livers (Figure 1A)
When primary hepatocytes were isolated from wild type and Brahma related gene 1 (BRG1) LKO mice and exposed to LPS + PA treatment, the induction of Sterol response element binding protein (SREBP) target genes and SREBP maturation were attenuated in the LKO cells compared to the WT cells (Figures 2E,F)

Summary

Introduction

Lipid is a major biological macromolecule that plays diverse roles in orchestrating differentiation, proliferation, migration, communication, survival, and death of mammalian cells (Glatz, 2011; Patil et al, 2019; Nechipurenko, 2020; Xie et al, 2020). The hepatocytes rely on thousands of proteins, which include transmembrane receptors, transcriptional regulators, and transporters, to coordinate lipid metabolism tailoring to various cellular events. This normally well-programmed process can BRG1 Regulates SCAP Transcription be hijacked by both intrinsic and extrinsic pathogenic stimuli to skew lipid metabolism and to promote the development of diseases (Neuschwander-Tetri, 2010; Mashek et al, 2015). Sterol response element binding protein (SREBP), initially identified and characterized by the Brown and Goldstein laboratory, represents a family of transcription factors considered master regulators of lipid metabolism (Shimano and Sato, 2017). Mice harboring over-expression of either SREBP1c or SREBP2 develop fatty liver (steatosis) spontaneously SREBP1c over-expression preferentially leads to an increase in plasma triglyceride levels whereas SREBP2 overexpression causes hypercholesterolemia (Horton et al, 2002a)

Methods

Results

Conclusion