A systems medicine approach to assessing functional metabolic changes during the development and progression of liver cirrhosis

• Applicants: Privatdozent Dr. Nikolaus Berndt; Dr. Madlen Matz-Soja
• Subject Area: Endocrinology, Diabetology, Metabolism ; Gastroenterology ; Medical Informatics and Medical Bioinformatics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534075507

Non-alcoholic steatohepatitis (NASH) is about to become the most common cause of chronic liver disease in the western world. NASH usually starts with the accumulation of fat (triglycerides) in the liver, which progresses to a chronic inflammatory state with varying degrees of fibrosis in about 20% of all cases, potentially ending up in cirrhosis and severe liver failure. Notably, the liver can maintain its multiple metabolic functions over a long period of NASH progression. This remarkable metabolic reserve capacity of the liver is due to an up-regulation of metabolic capacities in the permanently shrinking fraction of hepatocytes. Metabolic dysfunction of the liver associated with clinical symptoms like jaundice, ascites, or neurological disorders will occur if this compensation collapses, and increased metabolic competence on the cellular level cannot compensate for the drop in supply of nutrients and oxygen due to structural changes of the liver tissue. Better understanding this intriguing interplay between structural and functional changes of the liver during NASH progression is the objective of this project. We will assess how cellular and structural changes behave in realistic liver fibrosis mouse models and evaluate how they translate into the human situation. By combining systems biochemistry, functional assays, and computational modeling, we will explore and delineate how the cellular and structural changes affect the short- and long-term regulation of hepatic central metabolism, including carbohydrate metabolism, lipid metabolism, amino acid metabolism, and ammonia and alcohol detoxification. From liver samples, we will generate protein abundance data by mass spectrometry and structural parameters from histology to generate individualized liver models on the cellular and tissue level. We will use these models to evaluate liver metabolism and use functional biochemical assays for validation. From our preliminary data, we suspect that structural changes hindering proper liver function will be, in part, compensated by metabolic adjustments occurring in individual hepatocytes. Only when a critical point is reached, and cellular compensation of structural deterioration is not possible anymore, do the clinical symptoms occur. We aim to rate at what stage a specific liver is in before reaching this critical point. We will apply our procedure to human liver specimens of different stages of liver fibrosis and cirrhosis from patients undergoing liver surgery. We will compare the proteomic and structural fingerprints, as well as the functional liver states between the different clinical groups (degree of fibrosis, steatosis, and inflammation) with the different stages of the animal models to investigate the transferability of the animal model to the human situation.

• DFG Programme: Research Grants