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Smoothened Deficiency Accelerates Fas‐Induced Liver Injury

Hedgehog (Hh) signaling pathway is considered to be inactive in adult healthy liver, but it is activated after acute and chronic liver injury. Here, we reported that hepatocyte specific Smo deficiency accelerated Fas‐induced liver injury. Hepatocyte Smo deficiency (Smo KO) mice showed higher mortality, more serum transaminases, more apoptotic hepatocytes, more cleavage of caspases and PARP than wild type (WT) mice after Jo2 treatment. The liver tissues from Jo2‐treated Smo KO mice expressed lower levels of NK‐κB, EGFR and p‐Akt. Hh pathway was activated in the WT mice but not in the Smo KO mice after Jo2 injection. NK‐κB activation was Smo and Gli1 dependent. NK‐κB can bind to the EGFR promoter. Overexpression NK‐κB in Smo KO mice blocked Jo2‐induced liver injury. The primary hepatocytes isolated from Smo KO mice also accelerated Fas‐induced apoptosis in vitro in comparison to hepatocyte from WT mice. Smo KO hepatocytes showed lower levels of NK‐κB, EGFR and p‐Akt after Jo2 treatment compared with WT hepatocytes. These findings demonstrate that Hh pathway plays an important role in hepatocyte. Hh pathway was activated after Jo2 treatment. Smo deficiency in hepatocytes accelerated Fas‐induced apoptosis both in vivo and in vitro due to the inhibition of NK‐κB/EGFR/Akt pathway.