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Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan

Author

Listed:
  • Chensu Wang

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Hanspeter Niederstrasser

    (University of Texas Southwestern Medical Center)

  • Peter M. Douglas

    (Department of Molecular Biology, University of Texas Southwestern Medical Center)

  • Rueyling Lin

    (Department of Molecular Biology, University of Texas Southwestern Medical Center)

  • Juan Jaramillo

    (Department of Molecular Biology, University of Texas Southwestern Medical Center)

  • Yang Li

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Nathaniel W. Oswald

    (University of Texas Southwestern Medical Center)

  • Anwu Zhou

    (University of Texas Southwestern Medical Center)

  • Elizabeth A. McMillan

    (University of Texas Southwestern Medical Center)

  • Saurabh Mendiratta

    (University of Texas Southwestern Medical Center)

  • Zhaohui Wang

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Tian Zhao

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Zhiqaing Lin

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Min Luo

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Gang Huang

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Rolf A. Brekken

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Bruce A. Posner

    (University of Texas Southwestern Medical Center)

  • John B. MacMillan

    (University of Texas Southwestern Medical Center)

  • Jinming Gao

    (Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center)

  • Michael A. White

    (University of Texas Southwestern Medical Center)

Abstract

Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca2+-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.

Suggested Citation

  • Chensu Wang & Hanspeter Niederstrasser & Peter M. Douglas & Rueyling Lin & Juan Jaramillo & Yang Li & Nathaniel W. Oswald & Anwu Zhou & Elizabeth A. McMillan & Saurabh Mendiratta & Zhaohui Wang & Tian, 2017. "Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02332-3
    DOI: 10.1038/s41467-017-02332-3
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    Cited by:

    1. Ting Li & Dingyi Lu & Chengcheng Yao & Tingting Li & Hua Dong & Zhan Li & Guang Xu & Jiayi Chen & Hao Zhang & Xiaoyu Yi & Haizhen Zhu & Guangqin Liu & Kaiqing Wen & Haixin Zhao & Jun Gao & Yakun Zhang, 2022. "Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yoshito Minami & Atsushi Hoshino & Yusuke Higuchi & Masahide Hamaguchi & Yusaku Kaneko & Yuhei Kirita & Shunta Taminishi & Toshiyuki Nishiji & Akiyuki Taruno & Michiaki Fukui & Zoltan Arany & Satoaki , 2023. "Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Laurent L’homme & Benan Pelin Sermikli & Joel T. Haas & Sébastien Fleury & Sandrine Quemener & Valentine Guinot & Emelie Barreby & Nathalie Esser & Robert Caiazzo & Hélène Verkindt & Benjamin Legendre, 2024. "Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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