Store-Operated Ca²⁺ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism

Ca²⁺ signals were reported to control lipid homeostasis, but the Ca²⁺ channels and pathways involved are largely unknown. Store-operated Ca²⁺ entry (SOCE) is a ubiquitous Ca²⁺ influx pathway regulated by stromal interaction molecule 1 (STIM1), STIM2, and the Ca²⁺ channel ORAI1. We show that SOCE-deficient mice accumulate pathological amounts of lipid droplets in the liver, heart, and skeletal muscle. Cells from patients with loss-of-function mutations in STIM1 or ORAI1 show a similar phenotype, suggesting a cell-intrinsic role for SOCE in the regulation of lipid metabolism. SOCE is crucial to induce mobilization of fatty acids from lipid droplets, lipolysis, and mitochondrial fatty acid oxidation. SOCE regulates cyclic AMP production and the expression of neutral lipases as well as the transcriptional regulators of lipid metabolism, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and peroxisome proliferator-activated receptor α (PPARα). SOCE-deficient cells upregulate lipophagy, which protects them from lipotoxicity. Our data provide evidence for an important role of SOCE in lipid metabolism.