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

Ning Liang, Anastasius Damdimopoulos, Saioa Goñi, Zhiqiang Huang, Lise-Lotte Vedin, Tomas Jakobsson, Marco Giudici, Osman Ahmed, Matteo Pedrelli, Serena Barilla, Fawaz Alzaid, Arturo Mendoza, Tarja Schröder, Raoul Kuiper, Paolo Parini, Anthony Hollenberg, Philippe Lefebvre, Sven Francque, Luc Gaal, Bart Staels, Nicolas Venteclef, Eckardt Treuter () and Rongrong Fan ()
Additional contact information
Ning Liang: Karolinska Institutet
Anastasius Damdimopoulos: Karolinska Institutet
Saioa Goñi: Karolinska Institutet
Zhiqiang Huang: Karolinska Institutet
Lise-Lotte Vedin: Karolinska Institutet
Tomas Jakobsson: Karolinska Institutet
Marco Giudici: Karolinska Institutet
Osman Ahmed: Karolinska Institutet
Matteo Pedrelli: Karolinska Institutet
Serena Barilla: Karolinska Institutet
Fawaz Alzaid: Université Paris Diderot
Arturo Mendoza: Weill Cornell Medicine
Tarja Schröder: Karolinska Institutet
Raoul Kuiper: Karolinska Institutet
Paolo Parini: Karolinska Institutet
Anthony Hollenberg: Weill Cornell Medicine
Philippe Lefebvre: Institut Pasteur de Lille, U1011-EGID
Sven Francque: University of Antwerp
Luc Gaal: University of Antwerp
Bart Staels: Institut Pasteur de Lille, U1011-EGID
Nicolas Venteclef: Université Paris Diderot
Eckardt Treuter: Karolinska Institutet
Rongrong Fan: Karolinska Institutet

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09524-z

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