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

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

Author information

1
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden.
2
Department of Laboratory Medicine, Karolinska Institutet, Huddinge, 14157, Sweden.
3
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, 75013, France.
4
Division of Endocrinology, Diabetes and Metabolism, Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, 10021, USA.
5
Department of Medicine Huddinge, Karolinska Institutet, Huddinge, 14157, Sweden.
6
Inflammation and Infection Theme, Karolinska University Hospital, Huddinge, 14157, Sweden.
7
University Lille, INSERM, CHU Lillie, Institut Pasteur de Lille, U1011-EGID, Lille, F-59000, France.
8
Department of Gastroenterology and Hepatology, University of Antwerp, Antwerp, 2610, Belgium.
9
Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, 2610, Belgium.
10
Department of Endocrinology, Diabetology and Metabolism, University of Antwerp, Antwerp, 2610, Belgium.
11
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden. eckardt.treuter@ki.se.
12
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden. rongrong.fan@ki.se.

Abstract

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.

PMID:
30975991
PMCID:
PMC6459876
DOI:
10.1038/s41467-019-09524-z
[Indexed for MEDLINE]
Free PMC Article

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