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- Title
Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα.
- Authors
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
- 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. Dysregulation of PPARα dependent fatty acid oxidation promotes hepatic steatosis. Here the authors show that GPS2 inhibits PPARα activity and that ablation of GPS2 ameliorates hepatic steatosis in mice.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-09524-z