Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease [scRNA-Seq]

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance (IR), but little is known about the key genetic driver that links these two disorders. We aimed to elucidate the mechanism by which Smoothened (Smo), a G-protein coupled receptor, contributes to pathogenesis of NAFLD and IR. We used Smoflox/flox mice in combination with AAV8-TBG-Cre which enables genetic disruption of Smo in mature hepatocytes selectively. Adult Smoflox/flox mice were treated with AAV vectors for 7 days. Their livers were analyzed by histology, immunoblots, qPCR and single-cell RNA sequencing. We also performed RNA sequencing of 368 liver samples from controls and patients with NAFLD to assess the association of Smo expression with liver inflammation and fibrosis.