title: Store-Operated Ca2+Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism.
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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mate
authors.initials: M
authors.lastname: Maus
authors.affiliation: Department of Pediatrics, Zagreb University Hospital Centre and School of Medicine, 10 000 Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Cuk
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Bindi
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jayson
authors.initials: J
authors.lastname: Lian
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ouimet
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kaufmann
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Hue-Tran
authors.initials: HT
authors.lastname: Hornig-Do
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Moore
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Cuervo
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: feskes01@nyumc.org.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008049:Lipase / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism; D008066:Lipolysis / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D008049:Lipase; D000262:Adenylyl Cyclases; D002118:Calcium
keywords: CRAC channel; ORAI1; STIM1; cAMP; calcium; fatty acid oxidation; lipid metabolism; lipolysis; lipophagy; mitochondria