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Title
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Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPAR alpha
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Author
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Abstract
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| 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 alpha (PPAR alpha, 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-PPAR alpha partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest. |
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Language
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English
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Source (journal)
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Nature communications
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Publication
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2019
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ISSN
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2041-1723
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DOI
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10.1038/S41467-019-09524-Z
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Volume/pages
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10
(2019)
, 14 p.
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Article Reference
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1684
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ISI
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000464093800015
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Pubmed ID
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30975991
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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