dc.contributor.author | Madsen, Andre | en_US |
dc.contributor.author | Bozickovic, Olivera | en_US |
dc.contributor.author | Bjune, Jan Inge | en_US |
dc.contributor.author | Mellgren, Gunnar | en_US |
dc.contributor.author | Sagen, Jørn V. | en_US |
dc.date.accessioned | 2016-04-15T07:51:54Z | |
dc.date.available | 2016-04-15T07:51:54Z | |
dc.date.issued | 2015-11-09 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | https://hdl.handle.net/1956/11915 | |
dc.description.abstract | The 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.iso | eng | eng |
dc.publisher | Nature Publishing Group | eng |
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.rights | Attribution CC BY | eng |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0 | eng |
dc.title | Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2) | en_US |
dc.type | Peer reviewed | |
dc.type | Journal article | |
dc.date.updated | 2016-04-15T07:36:48Z | |
dc.description.version | publishedVersion | en_US |
dc.source.articlenumber | 16430 | |
dc.identifier.doi | https://doi.org/10.1038/srep16430 | |
dc.identifier.cristin | 1315736 | |
dc.source.journal | Scientific Reports | |
dc.source.40 | 5 | |