Early growth response‐1 transcription factor promotes hepatic fibrosis and steatosis in long‐term ethanol‐fed Long‐Evans rats

Abstract Background Previous studies demonstrated that the L ong‐ E vans ( LE ) rats exhibited liver injury and lipid metabolic abnormalities after 8 weeks of ethanol feeding. Aims The goal of this study was to investigate if the LE rats develop more advanced hepatic abnormalities (e.g., fibrosis) after long‐term feeding with an ethanol‐containing L ieber– D e C arli diet. In addition, the contribution of early growth response‐1 ( EGR 1) transcription factor to these pathological changes was assessed. Methods L ong‐ E vans rats were fed an ethanol‐containing or isocaloric control liquid diet for 18 months. Livers were processed for histological analyses, studies of fibrosis‐related gene expression, cell fractionation and triglyceride measurement. Serum alanine aminotransferase ( ALT ) levels were assessed. DNA binding activities of p53 and the sterol regulatory element‐binding protein‐1c ( SREBP 1c) were analysed. The abundance of EGR 1 and enzymes involved in fatty acid synthesis were determined. Chromatin immunoprecipitation was employed to study EGR 1 binding to the SREBP 1c promoter region. Results Ethanol feeding generated steatosis, chicken wire fibrosis and ALT elevations in the LE rats. Fibrosis was associated with the upregulation of EGR 1 and its downstream target genes. EGR 1 upregulation was associated with enhanced p53 activity and an increase in the cellular p66 shc abundance. Steatosis was linked to the activation of SREBP 1c. Importantly, EGR 1 upregulation paralleled the expression and transcriptional activity of SREBP 1c. Finally, EGR 1 was shown to bind to the SREBP 1c promoter region. Conclusions Long‐term ethanol feeding promoted steatosis and fibrosis in LE rats via EGR 1 activation. The highly abundant EGR 1 bound to the SREBP 1c promoter and contributed to the steatosis observed in the LE rat model.