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

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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.