VIVA SEMINAR

Tim Hardy

Supervisors: Prof Jelena Mann, Prof Derek Mann, Prof Quentin Anstee

Monday 25th February 13.30 - MED.L2.4, 2nd floor William Leech Building

THE ROLE OF DNA METHYLATION IN HEPATIC FIBROSIS PROGRESSION IN NON-ALCOHOLIC FATTY LIVER DISEASE

Non-alcoholic fatty liver disease is a common cause of liver dysfunction, with recent estimates suggesting that one quarter of the global population being affected. The incidence of NAFLD is rising, propelled by the same global forces driving the obesity epidemic, with which NAFLD is strongly associated. NAFLD broadly encompasses two distinct histological subtypes with differing severities; non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); the latter is defines fatty liver associated with hepatocyte injury, inflammation, and fibrosis. The prognosis of the disease is variable with the majority of patients having benign disease without associated liver-related morbidity and mortality. The presence of fibrosis remains the strongest predictor of outcome in NAFLD, and currently is best assessed by invasive liver biopsy.

Recent evidence suggests that epigenetic mechanisms, in particular DNA methylation may in part, play a role in modifying fibrosis progression, and therefore the course of the disease. In this project, the hypothesis was that DNA methylation plays a role in NAFLD fibrosis progression, and that this role may be exploited to develop non-invasive biomarkers of NAFLD fibrosis, which remains a key unmet need in NAFLD. First we investigated the role of differential DNA methylation signatures, within areas of human liver biopsy tissue. We then assessed the role and utility of differential DNA methylation in circulating plasma DNA in prediction of fibrosis stage in NAFLD patients. Lastly, we discovered novel whole genome plasma DNA methylation signatures associated with advanced fibrosis in NAFLD. In conclusion, our findings suggest that DNA methylation is important in the progression of NAFLD fibrosis and can be exploited as a biomarker of advanced fibrosis, a major unmet need in for NAFLD patients.