Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF- κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis.

Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF-κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis. Am J Pathol. 2018 Nov;188(11):2605-2616 Authors: Wang Y, Chen W, Han C, Zhang J, Song K, Kwon H, Dash S, Yao L, Wu T Abstract Although hedgehog (Hh) signaling pathway is inactive in adult healthy liver, it becomes activated during acute and chronic liver injury and, thus, modulates the reparative process and disease progression. We developed a novel mouse model with liver-specific knockout of Smoothened (Smo LKO), and animals were subjected to Fas-induced liver injury in vivo. Results showed that Smo deletion in hepatocytes enhances Fas-induced liver injury. Activation of Hh signaling in hepatocytes in the setting of Fas-induced injury was indicated by the fact that Jo2 treatment enhanced hepatic expression of Ptch1, Smo, and its downstream target Gli1 in control but not Smo LKO mice. Primary hepatocytes from control mice showed increased Hh signaling activation in response to Jo2 treatment in vitro. On the other hand, the Smo KO hepatocytes were devoid of Hh activation and were more susceptible to Jo2-induced apoptosis. The levels of NF-κB and related signaling molecules, including epidermal growth factor receptor and Akt, were lower in Smo KO livers/hepatocytes than in control livers/hepatocytes. Accordingly...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research