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

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

Nature communications (2018-04-14)
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, Myung-Shik Lee
摘要

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.

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单克隆抗-FLAG® M2 小鼠抗, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
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