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Liver Int. 2012 May;32(5):761-70. doi: 10.1111/j.1478-3231.2012.02752.x. Epub 2012 Jan 31.

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

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1
Division of Gastroenterology & Liver Research Center, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, RI, USA. Zoltan_Derdak@brown.edu

Abstract

BACKGROUND:

Previous studies demonstrated that the Long-Evans (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 Lieber-DeCarli diet. In addition, the contribution of early growth response-1 (EGR1) transcription factor to these pathological changes was assessed.

METHODS:

Long-Evans 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 (SREBP1c) were analysed. The abundance of EGR1 and enzymes involved in fatty acid synthesis were determined. Chromatin immunoprecipitation was employed to study EGR1 binding to the SREBP1c promoter region.

RESULTS:

Ethanol feeding generated steatosis, chicken wire fibrosis and ALT elevations in the LE rats. Fibrosis was associated with the upregulation of EGR1 and its downstream target genes. EGR1 upregulation was associated with enhanced p53 activity and an increase in the cellular p66(shc) abundance. Steatosis was linked to the activation of SREBP1c. Importantly, EGR1 upregulation paralleled the expression and transcriptional activity of SREBP1c. Finally, EGR1 was shown to bind to the SREBP1c promoter region.

CONCLUSIONS:

Long-term ethanol feeding promoted steatosis and fibrosis in LE rats via EGR1 activation. The highly abundant EGR1 bound to the SREBP1c promoter and contributed to the steatosis observed in the LE rat model.

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