Investigating the impact of PNPLA3 genetic polymorphism on the development and treatment of non-alcoholic steatohepatitis (NASH): an in vitro study using human stem cell-derived hepatic cells. (FWOAL923)

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Non- alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to life-threatening liver conditions including hepatic failure and cancer. Besides diet and lifestyle, a genetic polymorphism in the ‘patatin-like phospholipase domain-containing 3’ (PNPLA3) gene has recently been found to be associated with a higher susceptibility to NAFLD and up to a 10-fold increased risk of NAFLD progression to liver cancer. Hence, preventive and therapeutic strategies that efficiently counteract the clinical manifestation of NAFLD/NASH for people at high risk are urgently needed. However, a major hurdle in this regard is the lack of pre-clinical models that can accurately recapitulate the pathophysiology of NASH in humans, including genetic polymorphisms. To address this problem, we will generate human adult stem cell-derived hepatic cells with distinct PNPLA3 genetic backgrounds. These cells will subsequently be exposed in vitro to pro-NASH conditions in order to be able to elucidate the exact role of the PNPLA3 polymorphism in NASH development. Next, the influence of the PNPLA3 genetic variant on the effect of two anti-NASH drug candidates will be investigated. Improving the understanding of the genetic basis of human NASH will allow to facilitate risk stratification of affected patients, permit personalized treatment, and accelerate the development of new therapeutic strategies.

Keywords:liver disease

Disciplines:Hepatology