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

• Applicant: Dr. Aline Gottlieb
• Subject Area: Gastroenterology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414709986

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Svetlana Lutsenko