Defective STIM-mediated store operated Ca entry in hepatocytes leads to metabolic dysfunction in obesity.

Elife
Authors
Keywords
Abstract

Defective Ca handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca level is in part monitored by the store-operated Ca entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca 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 Ca balance and systemic metabolic control.

Year of Publication
2017
Journal
Elife
Volume
6
Date Published
2017 12 15
ISSN
2050-084X
DOI
10.7554/eLife.29968
PubMed ID
29243589
PubMed Central ID
PMC5777820
Links
Grant list
R01 DK052539 / DK / NIDDK NIH HHS / United States
R01 HL125753 / HL / NHLBI NIH HHS / United States
S10 RR029237 / RR / NCRR NIH HHS / United States
DK52539 / NH / NIH HHS / United States