Single-cell analysis of non-alcoholic fatty livers identifies a role for the constitutive androstane receptor

Abstract

Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. While several genetic risk factors have been identified, the cellular and molecular heterogeneity associated with the development of hepatic steatosis are still not fully understood. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic nonparenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression with unique molecular signatures of lipid synthesis. We find that NAFLD livers have elevated expression of the constitutive androstane receptor (CAR), a gene previously associated with lipid synthesis. Furthermore, nuclear expression of CAR positively correlates with steatohepatitis in humans. These findings demonstrate significant cellular differences in lipid signatures and identify a gene with a high likelihood of being linked to hepatic steatosis in humans.