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Cell Metab. 2017 Mar 7;25(3):698-712. doi: 10.1016/j.cmet.2016.12.021. Epub 2017 Jan 26.

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

Author information

1
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Pediatrics, Zagreb University Hospital Centre and School of Medicine, 10 000 Zagreb, Croatia.
3
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4
Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
5
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
6
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
7
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: feskes01@nyumc.org.

Abstract

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.

KEYWORDS:

CRAC channel; ORAI1; STIM1; cAMP; calcium; fatty acid oxidation; lipid metabolism; lipolysis; lipophagy; mitochondria

PMID:
28132808
PMCID:
PMC5342942
DOI:
10.1016/j.cmet.2016.12.021
[Indexed for MEDLINE]
Free PMC Article

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