Grb2-related adaptor protein GRAP is a novel regulator of liver fibrosis

Aims: Excessive liver fibrosis is frequently observed in chronic liver diseases and associated with decline of liver functions. Hepatic stellate cells (HSCs) are considered the principal mediator of liver fibrosis by trans -differentiating into myofibroblasts. In the present study we investigated the role of Grb2-related adaptor pro-tein (GRAP) in HSC activation and liver fibrosis.Methods and materials: Liver fibrosis was induced by carbon tetrachloride (CCl4) injection. Gene expression was examined by quantitative PCR. Cell proliferation was evaluated by EdU incorporation. DNA-protein interaction was examined by chromatin immunoprecipitation (ChIP).Key findings: GRAP expression was up-regulated during HSC-myofibroblast transition both in vivo and in vitro. Mechanistically, serum response factor (SRF) and myocardin-related transcription factor A (MRTF-A) formed a complex to bind to the GRAP promoter and activate GRAP transcription. Small interfering RNA (siRNA) mediated GRAP silencing blocked HSC-myofibroblast transition in vitro. Importantly, adeno-associated virus 6 (AAV6) mediated GRAP knockdown in myofibroblasts attenuated liver fibrosis in mice. Of note, inhibition of ERK signaling abrogated enhancement of HSC-myofibroblast transition by GRAP over-expression.Significance: Our data suggest that GRAP, possibly via ERK activation, regulates HSC-myofibroblast transition and contributes to liver fibrosis. Screening for small-molecule GRAP inhibitors may yield novel therapeutic solutions against liver fibrosis.

Automated summary

This study investigated the role of GRB2-related adaptor protein (GRAP) in hepatic stellate cell (HSC) activation and liver fibrosis. The results showed that GRAP expression was up-regulated during HSC-myofibroblast transition and that inhibition of GRAP blocked the transition. Additionally, knockdown of GRAP attenuated liver fibrosis in mice, and inhibition of ERK signaling abolished the enhancement of HSC-myofibroblast transition by GRAP over-expression.