Regulation of mice liver regeneration by early growth response-1 through the GGPPS/RAS/MAPK pathway

Background & Aims Liver regeneration (LR) consists of a series of complicated processes in which several transcription factors play important roles. Among them, the early growth response 1 gene (EGR-1) is rapidly induced in response to liver resection. Previous studies have shown that EGR-1−/− mice exhibit delayed hepatocellular mitotic progression after partial hepatectomy (PH). The mechanism underlying the EGR-1 regulated LR is still unknown. Our aim is to elucidate the underlying mechanism. Methods Mice infected with adenoviral vectors expressing GFP, EGR-1 or dominant negative EGR-1 (dnEGR-1) were subjected to 2/3 PH. The serum starvation recovery cell model was chosen to mimic the regeneration process for the in vitro studies. Cell proliferation and signaling pathways downstream of geranylgeranyl diphosphate synthase (GGPPS) were examined in the regenerating liver and serum starvation recovery cell model. Results Loss of function of EGR-1 significantly inhibited liver recovery and the expression of cyclin D1, cyclin E, and proliferating cell nuclear antigen (PCNA). The expression of GGPPS and the activity of the downstream RAS/MAPK pathway were inhibited in dnEGR-1-infected liver, which was consistent with the serum-induced cell model. In addition, loss of function of EGR-1 aggravated liver damage with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Conclusions EGR-1-induced GGPPS plays a vital role in the LR after PH through the RAS/MAPK signaling.