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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers

Author

Listed:
  • Hwan-Woo Park

    (University of Michigan)

  • Haeli Park

    (University of Michigan)

  • Ian A. Semple

    (University of Michigan)

  • Insook Jang

    (University of Michigan)

  • Seung-Hyun Ro

    (University of Michigan)

  • Myungjin Kim

    (University of Michigan)

  • Victor A. Cazares

    (University of Michigan)

  • Edward L. Stuenkel

    (University of Michigan)

  • Jung-Jae Kim

    (School of Computer Engineering, Nanyang Technological University)

  • Jeong Sig Kim

    (University of Michigan
    Soonchunhyang University Seoul Hospital)

  • Jun Hee Lee

    (University of Michigan)

Abstract

Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome–lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients.

Suggested Citation

  • Hwan-Woo Park & Haeli Park & Ian A. Semple & Insook Jang & Seung-Hyun Ro & Myungjin Kim & Victor A. Cazares & Edward L. Stuenkel & Jung-Jae Kim & Jeong Sig Kim & Jun Hee Lee, 2014. "Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5834
    DOI: 10.1038/ncomms5834
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    Cited by:

    1. Shiyan Liu & Mutian Chen & Yichang Wang & Yuqing Lei & Ting Huang & Yabin Zhang & Sin Man Lam & Huihui Li & Shiqian Qi & Jia Geng & Kefeng Lu, 2023. "The ER calcium channel Csg2 integrates sphingolipid metabolism with autophagy," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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