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

Mate Maus, Mario Cuk, Bindi Patel, Jayson Lian, Mireille Ouimet, Ulrike Kaufmann, Jun Yang, Rita Horvath, Hue Tran Hornig-Do, Zofia M. Chrzanowska-Lightowlers, Kathryn J. Moore, Ana Maria Cuervo, Stefan Feske

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)698-712
Number of pages15
JournalCell metabolism
Volume25
Issue number3
DOIs
StatePublished - Mar 7 2017

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Maus, M., Cuk, M., Patel, B., Lian, J., Ouimet, M., Kaufmann, U., Yang, J., Horvath, R., Hornig-Do, H. T., Chrzanowska-Lightowlers, Z. M., Moore, K. J., Cuervo, A. M., & Feske, S. (2017). Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell metabolism, 25(3), 698-712. https://doi.org/10.1016/j.cmet.2016.12.021