title: Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2).
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.
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, N-5021 Norway.|Department of Clinical Science, University of Bergen, N-5020 Norway.
authors.forename: Andre
authors.initials: A
authors.lastname: Madsen
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, N-5021 Norway.|Department of Clinical Science, University of Bergen, N-5020 Norway.
authors.forename: Olivera
authors.initials: O
authors.lastname: Bozickovic
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, N-5021 Norway.|Department of Clinical Science, University of Bergen, N-5020 Norway.
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Bjune
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, N-5021 Norway.|Department of Clinical Science, University of Bergen, N-5020 Norway.|KG Jebsen Center for Diabetes Research, University of Bergen, N-5020 Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.affiliation: Hormone Laboratory, Haukeland University Hospital, N-5021 Norway.|Department of Clinical Science, University of Bergen, N-5020 Norway.|KG Jebsen Center for Diabetes Research, University of Bergen, N-5020 Norway.
authors.forename: Jørn V
authors.initials: JV
authors.lastname: Sagen
mesh_terms: D053898:Biosynthetic Pathways / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D054890:Fatty Acid Synthase, Type I / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology*; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D007004:Hypoglycemic Agents; D051958:Nuclear Receptor Coactivator 2; D051780:Sterol Regulatory Element Binding Protein 1; D008687:Metformin; D002784:Cholesterol; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D005947:Glucose