TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiologic states

  1. Simiao Xu
  2. Yangyang Liu
  3. Ruixiang Hu
  4. Min Wang
  5. Oliver Stöhr
  6. Yibo Xiong
  7. Liang Chen
  8. Hong Kang
  9. Lingyun Zheng
  10. Songjie Cai
  11. Li He
  12. Cunchuan Wang
  13. Kyle D Copps
  14. Morris F White
  15. Ji Miao  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Tongji Medical College, Huazhong University of Science and Technology, China
  3. Harvard Medical School, United States
  4. Brigham and Women's Hospital, United States
  5. The First Affiliated Hospital of Jinan University, China

Abstract

The elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ is abundantly expressed in pericentral hepatocytes and its expression is markedly reduced by fasting. TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to the GR response element in gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate that hepatic TAZ inhibits GR-transactivation of gluconeogenic genes and coordinates gluconeogenesis in response to physiologic fasting and feeding.

Data availability

There are no sequencing or structural data generated in this manuscript. All data generated and analyzed are included in the manuscript.

Article and author information

Author details

  1. Simiao Xu

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yangyang Liu

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ruixiang Hu

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Min Wang

    Biliary-Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Oliver Stöhr

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yibo Xiong

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Liang Chen

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Hong Kang

    Systemic Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lingyun Zheng

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Songjie Cai

    Transplantation Research Center, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Li He

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Cunchuan Wang

    Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Kyle D Copps

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Morris F White

    Endocrinology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Ji Miao

    Endocrinology, Boston Children's Hospital, Boston, United States
    For correspondence
    ji.miao@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0869-4492

Funding

NIDDK (DK100539)

  • Ji Miao

NIDDK (DK124328)

  • Ji Miao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were performed with the approval of the Institutional Animal Care and Research Advisory Committee at Boston Children's Hospital (protocols 17-07-3413R and 20-07-4200R).

Reviewing Editor

  1. David E James, The University of Sydney, Australia

Publication history

  1. Received: April 1, 2020
  2. Preprint posted: May 14, 2020 (view preprint)
  3. Accepted: August 13, 2021
  4. Accepted Manuscript published: October 8, 2021 (version 1)
  5. Version of Record published: October 29, 2021 (version 2)

Copyright

© 2021, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Simiao Xu
  2. Yangyang Liu
  3. Ruixiang Hu
  4. Min Wang
  5. Oliver Stöhr
  6. Yibo Xiong
  7. Liang Chen
  8. Hong Kang
  9. Lingyun Zheng
  10. Songjie Cai
  11. Li He
  12. Cunchuan Wang
  13. Kyle D Copps
  14. Morris F White
  15. Ji Miao
(2021)
TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiologic states
eLife 10:e57462.
https://doi.org/10.7554/eLife.57462

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