Hepatocyte Early Growth Response 1 (EGR1) Regulates Lipid Metabolism in Nonalcoholic Fatty Liver Disease

Objective Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide due to significant increases in the prevalence of obesity, insulin resistance diabetes, and hyperlipidemia. A risk factor for NAFLD is insulin resistance as it promotes the excessive accumulation of lipids into the hepatocytes, causing cellular stress and death. As a stress response gene, early growth response 1 (EGR1) plays critical roles in inflammation and tissue repair. The aim for this study is to explore a novel role of hepatocyte EGR1 in the regulation of lipid metabolism in NAFLD. Methods Human microarray data from NCBI GEO database (accession #GSE48452) was used to obtain relative EGR1 expression in human normal and NAFLD livers. To determine the expression of EGR1 during the development of NAFLD, C57Bl6/J mice were fed a high in fat, cholesterol, and fructose (HFCF) for up to 9 months and EGR1 levels were examined. An in vitro insulin stimulation experiment was performed in wild type and Egr1 ‐deficient primary hepatocytes to assess insulin response. In vivo hepatocyte‐specific Egr1 knockout ( Egr1 ‐HKO) mice was accomplished in 2‐month‐old Egr1 flox/flox male mice by tail vein administration of adeno‐associated viral vector 8 (AAV8) expressing cre recombinase driven by thyroxine binding globulin (TBG) promoter (AAV8‐Tbg‐Cre). An empty vector AAV8‐Tbg‐Null was included as a control. WT and Egr1 ‐HKO mice were fed either a normal chow or HFCF diet for 5 months and followed by the examination of body composition, adiposity, metabolic rates, insulin sensitivity, and liver histology. Results EGR1 was dramatically induced by insulin and abundantly expressed in the postprandial liver. The expression of EGR1 was significantly reduced in human and mouse NAFLD livers, suggesting a biological relevance of EGR1 downregulation during the pathogenesis of NAFLD. In vitro hepatocyte cultures showed that Egr1 ‐deficient hepatocytes have impaired activation of AKT but enhanced de novo lipogenesis in response to insulin. In vivo knockout of hepatocyte‐specific Egr1 led to liver steatosis and increased whole body adiposity under the chow diet. Additionally, in vivo EGR1 deficiency in hepatocytes exacerbated NAFLD progression by promoting liver inflammation and fibrosis in mice fed a HFCF diet. Conclusions Our studies reveal a previously unrecognized role of hepatic EGR1 in the regulation of lipid metabolism. Our findings suggest that hepatocyte EGR1 is crucial to maintain hepatic insulin response and loss of EGR1 in hepatocytes leads to liver steatosis that exacerbates NAFLD development and progression. Support or Funding Information NCI K22CA184146 and NIH P20 GM103549 to Yuxia Zhang. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .