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

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Liang, Ning | Damdimopoulos, Anastasius | Goñi, Saioa | Huang, Zhiqiang | Vedin, Lise-Lotte | Jakobsson, Tomas | Giudici, Marco | Ahmed, Osman | Pedrelli, Matteo | Barilla, Serena | Alzaid, Fawaz | Mendoza, Arturo | Schröder, Tarja | Kuiper, Raoul | Parini, Paolo | Hollenberg, Anthony | Lefebvre, Philippe | Francque, Sven | van Gaal, Luc | Staels, Bart | Venteclef, Nicolas | Treuter, Eckardt | Fan, Rongrong

Edité par CCSD ; Nature Publishing Group -

International audience. 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.

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