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

研究铜诱导的体内肝组织代谢应激，以提高对铜脂肪变性轴的认识

• 批准号: 414709986
• 负责人: Dr. Aline Gottlieb
• 金额: --
• 依托单位: Department of Physiology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414709986?language=en
• 关键词: Study; copper; induced; metabolic; stress

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.

铜诱导的代谢应激是否促进肝脏脂肪变性？非酒精性脂肪性肝病（NAFLD）和进行性非酒精性脂肪性肝炎（NASH）将成为世界范围内的主要肝病，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）。 由于人体的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，而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。肝脏在人体铜的吸收、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稳态与脂肪变性之间的联系，但确切的病理生理学和分子机制仍不清楚。本项目的中心目标是了解ATP 7 B-/-敲除小鼠的铜代谢如何与脂肪变性相互作用。ATP 7 B（Wilson’s Disease Gene）是负责肝脏铜转运的基因，其功能障碍导致Wilson’s Disease的发展。 特别是铜超载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将被探索。为此，将在体内测量ATP 7 B-/-敲除小鼠和相应对照小鼠肝脏中不同细胞区室的代谢状态，例如糖酵解速率、线粒体功能和氧化应激，以确定疾病的三个阶段。在该项目的进一步步骤中，这些发现将与不同的小鼠队列进行比较，即ATP 7 B Delta hep小鼠，这是一种遗传性脂肪变性模型。通过这些比较，相似性和差异将出现，希望有助于了解铜失衡如何影响脂肪变性的发展。有了这些新的知识，应该有可能找到新的治疗方法，不仅有助于减少威尔逊病的脂肪变性发展，而且有助于NALFD。