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

铜诱导的代谢应激是否会促进肝脏脂肪变性？非酒精性脂肪性肝病（NAFLD）和进行性非酒精性脂肪性肝炎（NASH）将成为世界范围内主要的肝脏疾病，其典型的晚期并发症为纤维化、肝硬化，直至发展为肝细胞癌（HCC）。由于人体主要代谢器官受到影响，目前的预防和治疗主要集中在减肥上，没有药物治疗可以减缓疾病。铜是人体生理必需的微量元素。在人体器官中，肝脏在铜的吸收、分布和排泄中起着关键作用。不同的研究小组已经发现了铜体内平衡与脂肪变性之间的联系，但对确切的病理生理和分子机制的理解仍不清楚。该项目的中心目标是了解铜代谢如何与ATP7B-/-敲除小鼠的脂肪变性相互作用。ATP7B（威尔逊氏病基因）是负责铜在肝脏中的运输的基因，它的功能障碍导致威尔逊氏病的发展。特别是铜超载引起的氧化应激与肝细胞脂肪变性和脂肪生成之间的分子机制将被探讨。为此，将在体内测量ATP7B-/-敲除小鼠和相应对照小鼠的代谢状态，如糖酵解率、线粒体功能和肝脏中不同细胞区室的氧化应激。在该项目的进一步研究中，这些发现将与另一组小鼠进行比较，即ATP7B δ型肝小鼠，这是一种遗传性脂肪变性模型。通过这些比较，相似性和差异性将有望帮助理解铜失衡如何影响脂肪变性的发展。有了这些新获得的知识，应该有可能找到新的治疗方法，可以帮助减少脂肪变性的发展，不仅在威尔逊病中，而且在NALFD中。

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.