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

Liang, NingDamdimopoulos, AnastasiusGoñi Irigoyen, SaioaHuang, ZhiqiangVedin, Lise-LotteJakobsson, TomasGiudici, MarcoAhmed, OsmanPedrelli, MatteoBarilla, SerenaAlzaid, FawazMendoza, ArturoSchröder, TarjaKuiper, RaoulParini, PaoloHollenberg, AnthonyLefebvre, PhilippeFrancque, SvenVan Gaal, LucStaels, BartVenteclef, NicolasTreuter, EckardtFan, Rongrong2024-04-252024-04-252019Liang, 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.2041-172310.1038/s41467-019-09524-zhttps://academica-e.unavarra.es/handle/2454/48019Obesity 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.application/pdfeng© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License.Non-alcoholic fatty liver disease (NAFLD)Non-alcoholic steatohepatitisPPARαG protein pathway suppressor 2 (GPS2)Histone deacetylase 3 (HDAC3) complexGps2Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARαinfo:eu-repo/semantics/article2024-04-25info:eu-repo/semantics/openAccess