VITA for NAFLD PROJECT

FRRB Project 1749055 - A very innovative therapeutic approach for non-alcoholic fatty liver disease and its complications

PROJECT SUMMARY

Non-alcoholic fatty liver disease (NAFLD) common in Western countries is characterized by the accumulation of fat in the liver and is frequent in obese and diabetic patients. Inflammation, genetic susceptibility and alterations in iron metabolism contribute to its development and progression to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Unfortunately, there are no specific therapies. The liver is central in the regulation of lipid and iron metabolism, two closely related processes: an excess of iron in hepatocytes promotes dyslipidemia and NAFLD, while the increase in the signaling pathway that regulates the iron hormone hepcidin attenuates hepatosteatosis. The molecular mechanism is unknown, but we hypothesized that SUV420H, an epigenetic regulator of lipid metabolism that modulates the lipid transcription factor PPAR, could represent the crossroads between fatty liver disease and iron metabolism.  The aim of the project is to investigate the role of SUV420H in the development and progression of NAFLD in mouse models for prevention and treatment purposes. After generating Suv420h-deficient mice in the liver, we evaluated their response to a NAFLD-NASH-inducing diet. Mice lacking hepatic Suv420h respond more mildly to diet than controls, with reduced weight gain, less hepatomegaly and steatosis, and less hypertrophy of adipose tissue. They are also partially protected by NASH, with less fibrosis and inflammation, thus suggesting a protective effect to the development of NAFLD-NASH due to the absence of Suv420h. We have started a preclinical study to silence both methyltransferases and a hepcidin inhibitor in the liver, and preliminary results show that the use of these molecules partially protects against the progression of NAFLD towards steatohepatitis.