TY - JOUR
T1 - Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan
AU - Wang, Chensu
AU - Niederstrasser, Hanspeter
AU - Douglas, Peter M.
AU - Lin, Rueyling
AU - Jaramillo, Juan
AU - Li, Yang
AU - Olswald, Nathaniel W.
AU - Zhou, Anwu
AU - McMillan, Elizabeth A.
AU - Mendiratta, Saurabh
AU - Wang, Zhaohui
AU - Zhao, Tian
AU - Lin, Zhiqaing
AU - Luo, Min
AU - Huang, Gang
AU - Brekken, Rolf A.
AU - Posner, Bruce A.
AU - MacMillan, John B.
AU - Gao, Jinming
AU - White, Michael A.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-02332-3
DO - 10.1038/s41467-017-02332-3
M3 - Article
C2 - 29273768
AN - SCOPUS:85039417721
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2270
ER -