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Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity

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Cite this article as: eLife 2017;6:e29968 doi: 10.7554/eLife.29968

Abstract

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.

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Author details

  1. Ana Paula Arruda

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Benedicte Mengel Pers

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Günes Parlakgul

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ekin Güney

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ted Goh

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Erika Cagampan

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Grace Yankun Lee

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Renata L Goncalves

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Gökhan S Hotamisligil

    Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, United States
    For correspondence
    ghotamis@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2906-1897

Funding

National Institutes of Health (DK52539)

  • Gökhan S Hotamisligil

Pew Charitable Trusts

  • Ana Paula Arruda

Alfred Benzon Foundation

  • Benedicte Mengel Pers

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

Ethics

Animal experimentation: All in vivo studies are approved by the Harvard Medical Area Standing Committee on Animals under the protocols #02396 and #04779.

Reviewing Editor

  1. Michael Czech, University of Massachusetts Medical School, United States

Publication history

  1. Received: June 28, 2017
  2. Accepted: December 14, 2017
  3. Accepted Manuscript published: December 15, 2017 (version 1)
  4. Version of Record published: January 22, 2018 (version 2)

Copyright

© 2017, Arruda 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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