Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity
- Harvard T.H. Chan School of Public Health, United States
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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.
Article and author information
Author details
Gökhan S Hotamisligil
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
- Michael Czech, University of Massachusetts Medical School, United States
Publication history
- Received: June 28, 2017
- Accepted: December 14, 2017
- Accepted Manuscript published: December 15, 2017 (version 1)
- 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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