Study of the copper-induced metabolic stress on liver tissue in vivo to improve understanding of the copper-steatosis axis

非酒精性脂肪性肝病(NAFLD)和进展型非酒精性脂肪性肝炎(NASH)将成为世界范围内主要的肝病，其典型的晚期并发症为纤维化、肝硬变，直至发展为肝细胞癌(HCC)。由于人体的主要代谢器官受到影响，目前预防和治疗的重点是减肥，而没有药物疗法来减缓疾病。铜是人体生理所必需的微量元素。肝脏在人体对铜的吸收、分布和排泄中起着关键作用。不同的研究小组已经有一些发现将铜的稳态与脂肪变性联系起来，但对确切的病理生理和分子机制的了解仍然不清楚。本项目的中心目标是了解ATP7B/-基因敲除小鼠的铜代谢与脂肪变性的相互作用。ATP7B(肝豆状核变性基因)是负责铜在肝脏转运的基因，其功能障碍导致肝豆状核变性的发生。特别是探讨铜过量导致氧化应激与肝细胞脂肪变性和脂肪生成之间的分子机制。为此，将在体内测量ATP7B/-基因敲除小鼠和相应对照小鼠肝脏不同细胞隔室的代谢状态，如糖酵解率、线粒体功能和氧化应激，在三个定义的疾病阶段。在该项目的下一步，这些发现将与另一组小鼠进行比较，ATP7B Delta HEP小鼠是一种遗传脂肪变性模型。通过这些比较，相似之处和不同之处将显现出来，希望有助于理解铜失衡如何影响脂肪变性的发展。有了这些新的知识，应该可以找到新的治疗方法来帮助减少脂肪变性的发展，不仅在肝豆状核变性，而且在非酒精性肝病。

Does copper-induced metabolic stress promote liver steatosis?Non-alcoholic fatty liver disease (NAFLD) and the progressive form non-alcoholic steatohepatitis (NASH) will become the leading liver disease worldwide with its typical late stage complications of fibrosis, cirrhosis, and up to the development of hepatocellular carcinoma (HCC). As the main metabolic organ in the human body is affected, prevention and therapy are currently focused on weight loss, while no pharmacotherapy is available to slow down the disease. Copper is an essential trace element for human physiology. The liver plays a key role in copper uptake, distribution, and excretion in human organisms.There have been several findings in different research groups that link copper-homeostasis to steatosis, but the understanding of exact pathophysiological and molecular mechanisms remain unclear.The central objective of this project is to understand how the copper metabolism interacts with steatosis on the ATP7B-/- knockout mice. ATP7B (Wilson's Disease Gene) is the gene responsible for copper transportation in the liver and its malfunction causes the development of Wilson's Disease. Especially the molecular mechanisms between an overload of copper that cause oxidative stress and the development of steatosis in hepatocytes and lipogenesis will be explored.To this end the metabolic state, e.g. glycolysis rate, mitochondrial function and oxidative stress of different cell compartments in livers of ATP7B-/- knockout and corresponding control mice will be measured in vivo for the three defined disease stages. In a further step of the project these findings will be compared to a different mouse-cohort, the ATP7B Delta hep mice, which are a genetic steatosis model. Through these comparisons similarities and differences will appear that hopefully help understand how a copper misbalance influences the development of steatosis. With that new gained knowledge, it should be possible to find new therapeutic approaches that can help to decrease the development of steatosis, not just in Wilson's Disease, but also in NALFD.