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dc.contributor.authorMadsen, Andreen_US
dc.contributor.authorBozickovic, Oliveraen_US
dc.contributor.authorBjune, Jan Ingeen_US
dc.contributor.authorMellgren, Gunnaren_US
dc.contributor.authorSagen, Jørn V.en_US
dc.date.accessioned2016-04-15T07:51:54Z
dc.date.available2016-04-15T07:51:54Z
dc.date.issued2015-11-09
dc.identifier.issn2045-2322
dc.identifier.urihttps://hdl.handle.net/1956/11915
dc.description.abstractThe ability of the anti-diabetic drug metformin to inhibit anabolic processes including gluconeogenesis and lipogenesis is partly attributable to activation of the AMP-activated protein kinase (AMPK) pathway. The p160 steroid receptor coactivator 2 (SRC-2) is a key regulator of cellular metabolism and drives expression of the gluconeogenic enzyme glucose-6-phosphatase (G6Pc). Here, we uncovered a role for SRC-2 in the metabolic reprogramming imposed by metformin. In FaO cells, metformin dose-dependently reduced mRNA expression of SRC-2. Microarray analysis of metformin- treated cells revealed an overrepresentation of downregulated genes involved in biosynthesis of lipids and cholesterol. Several metformin-regulated genes including fatty acid synthase (FASN) were validated as transcriptional targets of SRC-2 with promoters characterized by sterol regulatory element (SRE) binding protein (SREBP) recognition sequences. Transactivation assays of the FASN promoter confirmed that SRC-2 is a coactivator of SREBP-1. By suppressing SRC-2 at the transcriptional level, metformin impeded recruitment of SRC-2 and RNA polymerase II to the G6Pc promoter and to SREs of mutual SRC-2/SREBP-1 target gene promoters. Hepatocellular fat accretion was reduced by metformin or knock-down of both SRC-2 and SREBP-1. Accordingly we propose that metformin inhibits glucose and lipid biosynthesis partly by downregulating SRC-2 gene expression.en_US
dc.language.isoengeng
dc.publisherNature Publishing Groupeng
dc.relation.ispartof<a href="http://hdl.handle.net/1956/11933" target="blank">Function and regulation of Steroid Receptor Coactivator 2. Transcriptional regulation of cellular metabolism</a>
dc.rightsAttribution CC BYeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0eng
dc.titleMetformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2)en_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2016-04-15T07:36:48Z
dc.description.versionpublishedVersionen_US
dc.source.articlenumber16430
dc.identifier.doihttps://doi.org/10.1038/srep16430
dc.identifier.cristin1315736
dc.source.journalScientific Reports
dc.source.405


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