The Hedgehog Signaling pathway in the adult liver- Studies on the influence on the hepatic lipid metabolism and the mTOR/insulin signaling cascade-

作为一个主要的代谢器官，肝脏能够通过其特殊的解剖结构来协调各种代谢过程。因此，不同的代谢过程发生在肝脏的不同区域，这导致了称为代谢分区的独特现象。根据最近的研究，除了氧和代谢物梯度外，形态发生的信号级联，如Wnt信号通路，也参与中枢代谢过程的分区。另一种在肝脏代谢中的重要性直到最近才被完全发掘的形态因子是Hedgehog （Hh）信号通路。这种形态因子控制胚胎发生过程，并在成体组织的癌变中起重要作用。对于许多器官，研究表明，在发育和成年阶段，Wnt和Hh的协同和/或拮抗相互作用对于调节代谢过程至关重要。基于这些原因，有一个合理的问题：Hh信号通路在成人肝脏中可能具有什么功能？为了回答这个问题，已经建立了小鼠模型，允许在肝细胞中特异性地激活或失活Hh信号通路。我们对这些动物的研究结果显示，脂质代谢发生了巨大变化，反映了非酒精性脂肪性肝病（NAFLD）的特征。鉴于这种相似性，我们得出结论，Hh信号通路的活性可能是NAFLD发展的一个指标，NAFLD的患病率约为30%，属于工业化国家最常见的肝脏病变。因此，阐明和理解Hh和NAFLD交叉的潜在机制是本研究的主要目标。此外，我们的初步分析表明Hh信号通路对mTOR/胰岛素信号级联有直接影响。在拟议研究的第二部分，计划调查由此产生的变化在多大程度上影响肝脏的能量代谢，并可能对整个生物体产生进一步的影响。总的来说，这些结果将有助于理解Hh信号通路对肝脏生理相关过程的调节。由于该通路在许多肿瘤的发生中也起着核心作用，因此在临床试验中测试信号级联的抑制剂非常有兴趣。然而，最近的报道表明，这些抑制剂的应用往往会导致意想不到的副作用。这些观察结果表明，目前人们对成人肝脏Hh通路的功能知之甚少，对成人器官整体代谢的抑制可能产生意想不到的后果。在这方面，计划研究的结果将进一步有助于更好地评估生理刺激和合成抑制剂降低Hh信号活性所引起的可能风险。

As a major metabolic organ the liver is capable, through its special anatomy, to coordinate various metabolic processes. Thereby, different metabolic processes occur in different zones of the liver which leads to the unique phenomenon called metabolic zonation. According to recent studies it is known that in addition to oxygen and metabolite gradients also morphogenic signaling cascades, such as the Wnt signaling pathway, are involved in the zonation of central metabolic processes. Another morphogen, whose importance in liver metabolism was until recently completely unexplored, is the Hedgehog (Hh) signaling pathway. This morphogen controls processes of embryogenesis and plays an important role in carcinogenesis of adult tissues. For many organs it could be shown that during development and in the adult stage, synergistic and / or antagonistic interactions of Wnt and Hh are essential to enable modulations of metabolic processes. For these reasons, there was a legitimate question: what functions the Hh signaling pathway in the adult liver may have. To answer this question, mouse models have been generated which allow an activation or inactivation of the Hh signalling pathway specifically in hepatocytes. The results from our studies of these animals show dramatic changes in lipid metabolism that reflect the features of non-alcoholic fatty liver disease (NAFLD). Given this similarity, we conclude that the activity of the Hh signaling pathway may be an indicator for the development of NAFLD which, with a prevalence of about 30%, belongs to the most common liver pathologies in industrialized countries. It is therefore a major goal of the proposed study to elucidate and understand the underlying mechanism of the intersection of Hh and NAFLD. In addition, our preliminary analyses show that the Hh signaling pathway has a direct impact on the mTOR/Insulin signaling cascade. In the second part of the proposed study it is planned to investigate to what extent the resulting changes affect the energy metabolism of the liver and may have further consequences for the whole organism. Collectively, the results will contribute to the understanding of the regulation of physiologically relevant processes in the liver by the Hh signaling pathway. As this pathway plays also a central role in the oncogenesis of many tumors, there is a great interest in testing the inhibitors of the signaling cascade in clinical trials. Recent reports, however, demonstrated that the application of these inhibitors often leads to unexpected side effects. These observations illustrate how less is still known today about the functions of the Hh pathway in adult liver and which unexpected consequences on the overall metabolism in adult organs its inhibition may have. In this respect, the results of the planned study will further contribute to a better assessment of possible risks caused by a reduction of the Hh signaling activity by physiological stimuli and synthetic inhibitors.