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Diabetes. 2014 Oct;63(10):3266-78. doi: 10.2337/db13-1283. Epub 2014 Jun 19.

Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1α.

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  • 1Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD.
  • 2Dana-Farber Cancer Institute, Boston, MA.
  • 3Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD.
  • 4Marlene 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.
  • 5Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD.
  • 6Dana-Farber Cancer Institute, Boston, MA Department of Genetics, Harvard Medical School, Boston, MA.
  • 7Marlene 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.

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.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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