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

eLife

Ekin Güney¹  Gökhan S Hotamisligil¹  Grace Yankun Lee¹  Ana Paula Arruda¹  Günes Parlakgul¹  Ted Goh¹  Renata L Goncalves¹  Benedicte Mengel Pers¹  Erika Cagampan¹ 

[1] Department of Genetics and Complex Diseases, Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, United States;

关键词: endoplasmic reticulum;    calcium;    obesity;    insulin resistance;    SOCE;   

DOI  :  10.7554/eLife.29968

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown