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

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dc.contributor.authorLiang, Ning
dc.contributor.authorDamdimopoulos, Anastasius
dc.contributor.authorGoñi Irigoyen, Saioa
dc.contributor.authorHuang, Zhiqiang
dc.contributor.authorVedin, Lise-Lotte
dc.contributor.authorJakobsson, Tomas
dc.contributor.authorGiudici, Marco
dc.contributor.authorAhmed, Osman
dc.contributor.authorPedrelli, Matteo
dc.contributor.authorBarilla, Serena
dc.contributor.authorAlzaid, Fawaz
dc.contributor.authorMendoza, Arturo
dc.contributor.authorSchröder, Tarja
dc.contributor.authorKuiper, Raoul
dc.contributor.authorParini, Paolo
dc.contributor.authorHollenberg, Anthony
dc.contributor.authorLefebvre, Philippe
dc.contributor.authorFrancque, Sven
dc.contributor.authorVan Gaal, Luc
dc.contributor.authorStaels, Bart
dc.contributor.authorVenteclef, Nicolas
dc.contributor.authorTreuter, Eckardt
dc.contributor.authorFan, Rongrong
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.date.accessioned2024-04-25T17:38:57Z
dc.date.available2024-04-25T17:38:57Z
dc.date.issued2019
dc.date.updated2024-04-25T16:36:16Z
dc.description.abstractObesity 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.en
dc.description.sponsorshipE.T. was supported by grants from the Center for Innovative Medicine (CIMED) at the Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Swedish Diabetes Foundation, the Novo Nordisk Foundation, and the European Union FP7 HEALTH project HUMAN. R. F. was supported by the European Foundation for the Study of Diabetes (EFSD)/Lilly research fellowship, Junior Diabetes Wellness Sverige grant and KI research foundation grants. R.K. and T.S. were supported by KI/SL and grants from CIMED. N.L. received a doctoral education grant (KID) from Karolinska Institutet. Z.H. was supported by Chinese Government Scholarship (CSC). N.V. was supported by grants from the French National Agency of Research (CONRAD and PROVIDE), Region Ile de France (CORDDIM), Paris city (EMERGENCE), the French Foundation for Diabetes (SFD), and the European Union H2020 framework (ERC-EpiFAT 725790). The human liver transcriptome study performed by P.L., F.A., N.V., and B.S. was supported by EU [HEPADIP (Contract LSHM-CT-2005-018734) and RESOLVE (Contract FP7-305707)], the European Research Council (ERC Grant Immunobile, contract 694717), Fondation pour la Recherche Médicale (Equipe labellisée, DEQ20150331724) and Agence Nationale pour la Recherche (ANR-10-LBEX-46). B.S. is a recipient of an Advanced ERC Grant (694717).en
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLiang, N., Damdimopoulos, A., Goñi, S., Huang, Z., Vedin, L.-L., Jakobsson, T., Giudici, M., Ahmed, O., Pedrelli, M., Barilla, S., Alzaid, F., Mendoza, A., Schröder, T., Kuiper, R., Parini, P., Hollenberg, A., Lefebvre, P., Francque, S., Van Gaal, L., Staels, B., Venteclef, N., Treuter, E., Fan, R. (2019) Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARa. Nature Communications, 10(1), 1-14. https://doi.org/10.1038/s41467-019-09524-z.en
dc.identifier.doi10.1038/s41467-019-09524-z
dc.identifier.issn2041-1723
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/48019
dc.language.isoengen
dc.publisherNature Researchen
dc.relation.ispartofNature Communications (2019), 10, 1684, 1-14en
dc.relation.projectIDinfo:eu-repo/grantAgreement/European Commission/Horizon 2020 Framework Programme/725790/
dc.relation.publisherversionhttps://doi.org/10.1038/s41467-019-09524-z
dc.rights© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License.en
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectNon-alcoholic fatty liver disease (NAFLD)en
dc.subjectNon-alcoholic steatohepatitisen
dc.subjectPPARαen
dc.subjectG protein pathway suppressor 2 (GPS2)en
dc.subjectHistone deacetylase 3 (HDAC3) complexen
dc.subjectGps2en
dc.titleHepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARαen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dspace.entity.typePublication
relation.isAuthorOfPublication7945ddd5-cf8b-4927-bd7a-4ade2fb61f11
relation.isAuthorOfPublication.latestForDiscovery7945ddd5-cf8b-4927-bd7a-4ade2fb61f11

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