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- Title
A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes.
- Authors
Yu-Mi Lim; Kook Hwan Kim; Jinyoung Kim; Hyejin Lim; Myung-Shik Lee; Kihyoun Park; Young Eui Jeon; Hui-Yun Hwang; Dong Jin Lee; Ho Jeong Kwon; Haushabhau Pagire; Jin Hee Ahn
- 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.
- Subjects
AUTOPHAGY; DIABETES; METABOLIC syndrome; HOMEOSTASIS; ORIGIN of life
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-03939-w