Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Am J Pathol. 2018 Nov;188(11):2605-2616. doi: 10.1016/j.ajpath.2018.07.018.
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, hydrodynamic gene delivery of active NK-κB prevented Jo2-induced liver injury in the Smo LKO mice. Our findings provide important evidence that adult hepatocytes become responsive to Hh signaling through up-regulation of Smo in the setting of Fas-induced liver injury and that such alteration leads to activation of NF-κB/epidermal growth factor receptor/Akt, which counteracts Fas-induced hepatocyte apoptosis.
尽管 Hedgehog（Hh）信号通路在成人健康肝脏中处于非激活状态，但在急性和慢性肝损伤时会被激活，从而调节修复过程和疾病进展。我们开发了一种新型的肝脏特异性 Smoothened（Smo）敲除小鼠模型（Smo LKO），并在体内对其进行 Fas 诱导的肝损伤。结果表明，肝细胞中 Smo 的缺失会增强 Fas 诱导的肝损伤。在 Fas 诱导的损伤中，Hh 信号在肝细胞中的激活表现在 Jo2 处理增强了控制而非 Smo LKO 小鼠中 Ptch1、Smo 及其下游靶基因 Gli1 的肝表达。来自对照小鼠的原代肝细胞在体外对 Jo2 处理显示出增加的 Hh 信号激活。另一方面，Smo KO 肝细胞缺乏 Hh 激活，并且对 Jo2 诱导的细胞凋亡更敏感。NF-κB 及其相关信号分子（包括表皮生长因子受体和 Akt）的水平在 Smo KO 肝脏/肝细胞中低于对照肝脏/肝细胞。因此，活性 NK-κB 的流体动力学基因传递可预防 Smo LKO 小鼠中 Jo2 诱导的肝损伤。我们的研究结果提供了重要证据，表明在 Fas 诱导的肝损伤中，成年肝细胞通过 Smo 的上调对 Hh 信号产生反应，并且这种改变会导致 NF-κB/表皮生长因子受体/Akt 的激活，从而抵消 Fas 诱导的肝细胞凋亡。
