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

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.