Ca 2+ signals were reported to control lipid homeostasis but the Ca 2+ channels and pathways involved are largely unknown. Store-operated Ca 2+ entry (SOCE) is a ubiquitous Ca 2+ influx pathway regulated by stromal interaction molecule 1 (STIM1) and STIM2, and by the Ca 2+ channel ORAI1. We show that SOCE-deficient mice accumulate pathological amounts of lipid droplets in 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 cAMP production and the expression of neutral lipases as well as the transcriptional regulators of lipid metabolism, PGC-1α and PPARα. SOCE-deficient cells upregulate lipophagy that protects them against lipotoxicity. Our data provide evidence for an important role of SOCE in lipid metabolism.
Calcium signaling is fundamental to many cellular processes and alterations in cellular Ca 2+ homeostasis occur in metabolic disorders. Maus et al delineate the role of store-operated calcium entry (SOCE), an important pathway for increasing intracellular Ca 2+ levels, in lipid metabolism in SOCE-deficient mice and cells from human patients.