Ubiquitin specific peptidase 47 contributes to liver regeneration

Aims: Hepatocytes resume proliferation following liver injuries to compensate for the loss of liver mass. Robust liver regeneration is an intrinsic and pivotal process that facilitates restoration of liver anatomy and function. In the present study we investigated the role of ubiquitin-specific peptidase 47 (USP47) in liver regeneration. Methods and materials: Proliferation of hepatocytes was evaluated by Ki67 staining in vivo and EdU incorporation in vitro. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP). Results: USP47 expression was up-regulated in hepatocytes isolated from mice subjected to partial hepatectomy (PHx) or exposed to HGF treatment. Ingenuity pathway analysis revealed E2F1 as a primary regulator of USP47 transcription. Reporter assay and ChIP assay confirmed that E2F1 directly bound to the USP47 promoter and activated USP47 transcription. Consistently, E2F1 knockdown abrogated USP47 induction by HGF. Compared to the wild type littermates, USP47 knockout mice displayed compromised liver regeneration following PHx. In addition, USP47 inhibition by a small-molecule compound impaired liver regeneration in mice. On the contrary, USP47 over-expression enhanced proliferation of hepatocytes in vitro and promoted liver regeneration in mice. Importantly, a positive correlation between USP47 expression and hepatocyte proliferation was identified in patients with acute liver failure (ALF). Significance: Our data suggest that USP47, transcriptionally activated by E2F1, plays an essential role in liver regeneration.