Store-Operated Ca 2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Calcium / metabolism*
  • Fatty Acids / metabolism
  • HEK293 Cells
  • Humans
  • Lipase / metabolism
  • Lipid Droplets / metabolism
  • Lipolysis / genetics*
  • Mice
  • Mitochondria / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / ultrastructure
  • Oxidation-Reduction
  • PPAR alpha / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Signal Transduction / genetics
  • Transcription, Genetic*
  • Up-Regulation / genetics

Substances

  • Fatty Acids
  • PPAR alpha
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Lipase
  • Adenylyl Cyclases
  • Calcium