A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes

Hyejin Lim, Yu-Mi Lim, Kook Hwan Kim, Young Eui Jeon, Kihyoun Park, Jinyoung Kim, Hui-Yun Hwang, Dong Jin Lee, Haushabhau Pagire, Ho Jeong Kwon, Jin Hee Ahn and Myung-Shik Lee ()
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Hyejin Lim: Severance Biomedical Science Institute
Yu-Mi Lim: Severance Biomedical Science Institute
Kook Hwan Kim: Severance Biomedical Science Institute
Young Eui Jeon: Yonsei University College of Dentistry
Kihyoun Park: SAIHST, Sungkyunkwan University
Jinyoung Kim: Severance Biomedical Science Institute
Hui-Yun Hwang: Yonsei University
Dong Jin Lee: Yonsei University
Haushabhau Pagire: Gwangju Institute of Science and Technology
Ho Jeong Kwon: Yonsei University
Jin Hee Ahn: Gwangju Institute of Science and Technology
Myung-Shik Lee: Severance Biomedical Science Institute

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Autophagy is a critical regulator of cellular homeostasis, dysregulation of which is associated with diverse diseases. Here we show therapeutic effects of a novel autophagy enhancer identified by high-throughput screening of a chemical library against metabolic syndrome. An autophagy enhancer increases LC3-I to LC3-II conversion without mTOR inhibition. MSL, an autophagy enhancer, activates calcineurin, and induces dephosphorylation/nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy gene expression. MSL accelerates intracellular lipid clearance, which is reversed by lalistat 2 or Tfeb knockout. Its administration improves the metabolic profile of ob/ob mice and ameliorates inflammasome activation. A chemically modified MSL with increased microsomal stability improves the glucose profile not only of ob/ob mice but also of mice with diet-induced obesity. Our data indicate that our novel autophagy enhancer could be a new drug candidate for diabetes or metabolic syndrome with lipid overload.

Date: 2018
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DOI: 10.1038/s41467-018-03939-w

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