title: A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells.
abstract: AMP-activated protein kinase (AMPK) and the NAD(+)-dependent histone/protein deacetylase sirtuin 1 (SIRT1) are metabolic sensors that can increase each other's activity. They are also both activated by the antidiabetic drug metformin and downregulated in the liver under conditions of nutrient excess (e.g., hyperglycemia, high-fat diet, obesity). In these situations, the abundance of the tumor suppressor p53 is increased; however, the relevance of this to the changes in AMPK and SIRT1 is not known. In the present study we investigated this question in HepG2 cells under high glucose conditions. Metformin induced activation of AMPK and SIRT1 and decreased p53 protein abundance. It also decreased triglyceride accumulation and cytosolic oxidative stress (a trigger for p53 accumulation) and increased the deacetylation of p53 at a SIRT1-targeted site. The decrease in p53 abundance caused by metformin was abolished by inhibition of murine double minute 2 (MDM2), a ubiquitin ligase that mediates p53 degradation, as well as by overexpression of a dominant-negative AMPK or a shRNA-mediated knockdown of SIRT1. In addition, overexpression of p53 decreased SIRT1 gene expression and protein abundance, as well as AMPK activity in metformin-treated cells. It also diminished the triglyceride-lowering action of metformin, an effect that was rescued by incubation with the SIRT1 activator SRT2183. Collectively, these findings suggest the existence of a novel reciprocal interaction between AMPK/SIRT1 and p53 that may have implications for the pathogenesis and treatment of metabolic diseases.
authors.affiliation: Endocrinology, Diabetes, and Nutrition Section, Department of Medicine, Boston University School of Medicine, Massachusetts, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Nelson
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Valentine
authors.forename: José M
authors.initials: JM
authors.lastname: Cacicedo
authors.forename: Marie-Soleil
authors.initials: MS
authors.lastname: Gauthier
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ido
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D034741:RNA, Small Interfering; C525423:SRT2183; C495901:TP53 protein, human; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D008687:Metformin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005947:Glucose