Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα

Nat Commun. 2019 Apr 11;10(1):1684. doi: 10.1038/s41467-019-09524-z.


Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopsy
  • Datasets as Topic
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Disease Progression
  • Epigenesis, Genetic
  • Fibrosis
  • HEK293 Cells
  • Hepatocytes / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipid Metabolism
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*


  • GPS2 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • PPAR alpha
  • Ppara protein, mouse