Gli1 is activated via the non‐classical TGFβ/smad 3 pathway rather than the sonic hedgehog pathway in a murine model of hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) is a serious neurological complication of liver failure. Our understanding of the events leading to HE is quite limited. The sonic hedgehog (Shh) pathway is upregulated during liver damage and Shh ligands have been found in the blood stream. Our aims were to evaluate the molecular changes leading to HE. Injection of azoxymethane (AOM) into mice caused liver damage and cognitive decline that culminated in coma. There was an increased release of Shh into the serum and an increase in Gli1 expression, the downstream effector of Shh signaling, in the neurons of the frontal cortex in the brain. Inhibition of Shh signaling inhibited the release of Shh ligands in the serum, but failed to prevent the activation of Gli1 or the neurological decline that occurred after AOM treatment. TGFβ could also be detected in the serum of AOM‐treated mice and resulted in the activation and nuclear translocation of SMAD3 in neurons of the frontal cortex. Pretreatment of mice with a neutralizing TGFβ antibody, prior to AOM injection prevented the activation of SMAD3, the increase of Gli1 expression and delayed the cognitive decline of the mice. These data suggest that during acute liver failure, TGFβ is released into the serum and may cause SMAD‐3 activation and the subsequent increase in Gli1 expression in the affected brain regions and that this sequence of events may be important in the neurological progression of HE to coma.