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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

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

Nat Commun. 2018 Apr 12;9(1):1438.

PMID: 29650965

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1234569095	Lalistat 2		1234569-09-5	Price

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