Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution
Laetitia Coassolo,
Tianyun Liu,
Yunshin Jung,
Nikki P. Taylor,
Meng Zhao,
Gregory W. Charville,
Silas Boye Nissen,
Hannele Yki-Jarvinen,
Russ B. Altman,
Katrin J. Svensson
Affiliations
Laetitia Coassolo
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, CA, USA
Tianyun Liu
Department of Bioengineering, Stanford University, Stanford, CA, USA
Yunshin Jung
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA
Nikki P. Taylor
Department of Bioengineering, Stanford University, Stanford, CA, USA
Meng Zhao
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, CA, USA
Gregory W. Charville
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
Silas Boye Nissen
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Hannele Yki-Jarvinen
Department of Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland
Russ B. Altman
Departments of Bioengineering, Genetics & Medicine, Stanford University, Stanford, CA, USA
Katrin J. Svensson
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, CA, USA; Corresponding author
Summary: Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic non-parenchymal 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. Surprisingly, the canonical lipid synthesis driver Srebp1 is not predictive of hepatic lipid accumulation, suggestive of other drivers of lipid metabolism. By combining transcriptional data at single-cell resolution with computational network analyses, we find that NAFLD is associated with high constitutive androstane receptor (CAR) expression. Mechanistically, CAR interacts with four functional modules: cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response. Nuclear expression of CAR positively correlates with steatohepatitis in human livers. These findings demonstrate significant cellular differences in lipid signatures and identify functional networks linked to hepatic steatosis in mice and humans.
