title: Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1α.
abstract: Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin D1 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1α is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1α and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Kavita
authors.initials: K
authors.lastname: Bhalla
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Liu
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Keyata
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Lars
authors.initials: L
authors.lastname: Anders
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Srikripa
authors.initials: S
authors.lastname: Devarakonda
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Ruby
authors.initials: R
authors.lastname: Dewi
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Buckley
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Bor-Jang
authors.initials: BJ
authors.lastname: Hwang
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Brian
authors.initials: B
authors.lastname: Polster
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD Department of Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, MD.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: Yezhou
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA Department of Genetics, Harvard Medical School, Boston, MA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY geoffrey.girnun@stonybrookmedicine.edu.
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Girnun
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000378:metabolism; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D005947:Glucose