Genome wide in-vivo functional genetic screen to identify novel modulators of Non-Alcoholic Fatty Liver Disease (NAFLD)

Abstract

The rising incidence of non-alcoholic fatty liver disease (NAFLD) globally, specifically its advanced form, non-alcoholic steatohepatitis, is the representative cause of the increasing demand for liver transplantation. Characterised by excessive fat accumulation without clinically significant alcohol consumption, NAFLD remains a challenging healthcare burden due to the lack of therapeutics available. A distinctive phenomenon seen in NAFLD patients is the aberrant regenerative capability of the liver which limits compensation of lost liver mass leading to liver failure. Here, we identified five novel gene candidates that were postulated to regulate liver regeneration through the preliminary small hairpin RNAs (shRNA) mediated functional genetic screen. Effects caused by the shRNA-mediated knockdown of these candidates were validated through in vitro cell proliferation and migration assays. Downregulation of Targets 01, 02 and 03 robustly increased the proliferative and migratory capacity of hepatocytes. Conversely, downregulation of Slc35b3 significantly reduced cell growth and migration while function of Pcolce remains elusive due to poor efficacy of its shRNA. These results suggest that depletion of Targets 01, 02 and 03 can potentially be a viable treatment option to restore liver regenerative capacity in NAFLD patients and therefore demands further investigation to uncover new insights underlying NAFLD development and disease progression.