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

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 Zhao, Zhiqaing Lin, Min Luo, Gang Huang, Rolf A. Brekken, Bruce A. Posner, John B. MacMillan, Jinming Gao () and Michael A. White ()
Additional contact information
Chensu Wang: Simmons Comprehensive Cancer 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
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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02332-3

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