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Metabolism

O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis

  1. Jagannath Misra1,
  2. Don-Kyu Kim1,
  3. Yoon Seok Jung1,
  4. Han Byeol Kim2,
  5. Yong-Hoon Kim3,
  6. Eun-Kyung Yoo4,
  7. Byung Gyu Kim5,
  8. Sunghoon Kim6,
  9. In-Kyu Lee4,
  10. Robert A. Harris7,
  11. Jeong-Sun Kim8,
  12. Chul-Ho Lee3,
  13. Jin Won Cho2 and
  14. Hueng-Sik Choi1⇑
  1. 1National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
  2. 2Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, Republic of Korea
  3. 3Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  4. 4Department of Internal Medicine, Kyungpook National University School of Medicine, Deagu, Republic of Korea
  5. 5Leading-edge Research Center for Drug Discovery and Development and Metabolic Disease, Kyungpook National University, Daegu, Korea
  6. 6Medicinal Bioconvergence Research Center Department of Molecular Medicine and Biopharmaceutical Sciences Graduate School of Convergence Science and Technology College of Pharmacy, Seoul National University, Seoul, Korea
  7. 7Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Roudebush VA Medical Center, Indianapolis, IN
  8. 8Department of Chemistry and Institute of Basic Sciences, Chonnam National University, Gwangju, Republic of Korea
  1. Corresponding author: Hueng-Sik Choi, hsc{at}chonnam.ac.kr.
Diabetes 2016 Oct; 65(10): 2835-2848. https://doi.org/10.2337/db15-1523
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Abstract

Estrogen-related receptor γ (ERRγ) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein O-GlcNAcylation. In this study, we demonstrate that ERRγ is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRγ recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRγ ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRγ protein and blocks the ability of ERRγ to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERRγ by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRγ-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRγ serves as a major signal to promote hepatic gluconeogenesis.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1523/-/DC1.

  • Received November 4, 2015.
  • Accepted June 15, 2016.
  • © 2016 by the American Diabetes Association.
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O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis
Jagannath Misra, Don-Kyu Kim, Yoon Seok Jung, Han Byeol Kim, Yong-Hoon Kim, Eun-Kyung Yoo, Byung Gyu Kim, Sunghoon Kim, In-Kyu Lee, Robert A. Harris, Jeong-Sun Kim, Chul-Ho Lee, Jin Won Cho, Hueng-Sik Choi
Diabetes Oct 2016, 65 (10) 2835-2848; DOI: 10.2337/db15-1523

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O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis
Jagannath Misra, Don-Kyu Kim, Yoon Seok Jung, Han Byeol Kim, Yong-Hoon Kim, Eun-Kyung Yoo, Byung Gyu Kim, Sunghoon Kim, In-Kyu Lee, Robert A. Harris, Jeong-Sun Kim, Chul-Ho Lee, Jin Won Cho, Hueng-Sik Choi
Diabetes Oct 2016, 65 (10) 2835-2848; DOI: 10.2337/db15-1523
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