Research Projects

Nonalcoholic fatty liver disease (NAFLD) is a significant cause of liver-related morbidity and mortality, with two principal phenotypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Up to 40% of those with NAFL progress to NASH and develop progressive fibrosis and cirrhosis. NASH is rapidly increasing as an etiology for end-stage liver disease and hepatocellular cancer requiring liver transplantation. Recent findings have demonstrated the upregulation of AATF in human liver tissues of NASH subjects compared to the control. AATF plays a crucial role in cell proliferation and survival by inducing cell cycle arrest, DNA repair, autophagy, and inhibition of apoptosis. However, the potential role of AATF in the progression of NASH remains unknown. The study aims to demonstrate whether loss of function of hepatic AATF improves insulin sensitivity and NASH endpoints using in vitro and in vivo models. The loss of function of hepatic AATF will be assessed in mice models of NAFLD using lipid nanoparticle (LNP)-based delivery of siRNA (siControl-LNP and siAATF-LNP) in vivo and in stable Huh7 cell clones (control and AATF knockdown) in vitro. RNA sequencing will be used to identify genes differentially regulated by AATF and detect levels of multiple inflammatory cytokines regulated by AATF in NASH. Successful completion of the proposed studies will provide in-depth insight into the molecular mechanism by which AATF promotes NASH and help establish AATF inhibition as a potential effective therapeutic strategy for NASH.