Data_Sheet_1_The Chromatin Remodeling Protein BRG1 Regulates SREBP Maturation by Activating SCAP Transcription in Hepatocytes.PDF

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.

固醇反应元件结合蛋白（Sterol response element binding protein, SREBP）是细胞脂质生成的核心调控因子。SREBP活性调控的关键环节之一，是其在包括SREBP裂解激活蛋白（SREBP cleavage activating protein, SCAP）在内的多种蛋白酶介导下发生的依次裂解与转位过程。本课题组此前已报道，Brahma相关基因1（Brahma related gene 1, BRG1）可直接与SREBP1c及SREBP2发生相互作用，在肝细胞中激活促脂质生成转录。本研究在此报道，在两种非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）小鼠模型中，BRG1缺失会导致小鼠肝脏内SREBP的成熟过程受阻及核积累水平降低。将肝细胞暴露于脂多糖（lipopolysaccharide, LPS）与棕榈酸（palmitate, PA）后，可促进SREBP的核积累；而BRG1敲低或抑制则会阻断SREBP的成熟过程。进一步分析显示，BRG1在SCAP的表达调控中发挥不可或缺的关键作用。机制层面研究表明，BRG1可与转录因子Sp1结合，并直接结合至SCAP启动子区域以激活SCAP的转录。对外源SCAP进行过表达后，BRG1敲除肝细胞中SREBP靶基因的表达缺陷可得到部分挽救。综上，本研究数据揭示了BRG1通过SREBP依赖途径参与脂质代谢调控的全新机制。