Role and functions of MCRS1 in liver disease

Resum

The liver is one of the major metabolic organs in the body. Among its functions, we find detoxification of compounds, production of enzymes and metabolites important for digestion and nutrient processing, and energy metabolism. It is a quiescent organ during homeostasis, however, its regenerative capacity increases during injury. Different factors can trigger damage in the liver, including hepatitis B and C virus infection, alcohol abuse and toxin poisoning. During liver injury, fibrotic and regenerative responses of the tissue play an essential role in the recovery of homeostasis. When the damage gets chronic, fibrosis progresses to cirrhosis, which leads to impairment of liver function. Cirrhosis is clinically considered a risk factor for the development of hepatocellular carcinoma (HCC). However, only 1-3% of patients with cirrhotic liver undergo into HCC development. Due to the lack of genetic mouse models of cirrhosis recapitulating features of the human disease, mechanisms of this disease and its contribution to liver cancer are still poorly understood. In this thesis project, we generated the first genetic mouse model of liver cirrhosis by depleting MCRS1 protein specifically in hepatocytes. Using this unique genetic tool, we dissected the events that lead to cirrhosis and cancer. In particular, we described that MCRS1 is an essential regulator of liver homeostasis that binds to chromatin to modulate gene expression through histone acetylation. MCRS1 loss increases histone acetylation in regulatory regions of bile acid transporter genes, altering their expression and causing bile acid accumulation in the liver, cell injury and fibrosis. Moreover, MCRS1 depletion downregulates the urea cycle, impairing the detoxification of ammonia and causing toxic hyperammonemia. Finally, we described that MCRS1 loss protects from tumorigenesis, whereas MCRS1 overexpression increases tumor burden in mice. MCRS1 is also expressed in human HCC samples and correlated with proliferative capacity. These findings shed light into the relationship between cirrhosis and HCC, suggesting that cirrhosis might be a protective mechanism during tumor progression. The usage of compounds that modulate MCRS1 expression may represent a new therapeutic approach in the treatment of cirrhosis and HCC, impacting patients’ quality of life and survival.