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

• Published in: Nature communications Vol. 9; no. 1; pp. 1438 - 14
• Main Authors: Lim, Hyejin, Lim, Yu-Mi, Kim, Kook Hwan, Jeon, Young Eui, Park, Kihyoun, Kim, Jinyoung, Hwang, Hui-Yun, Lee, Dong Jin, Pagire, Haushabhau, Kwon, Ho Jeong, Ahn, Jin Hee, Lee, Myung-Shik
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 12.04.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animal models; Animals; Autophagy; Autophagy - drug effects; Calcineurin; Chemical compounds; Dephosphorylation; Diabetes; Diabetes mellitus; Diabetes Mellitus - drug therapy; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Gene expression; HeLa Cells; High-throughput screening; Homeostasis; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Inflammasomes; Lipid Metabolism - drug effects; Male; Metabolic syndrome; Metabolic Syndrome - drug therapy; Metabolic Syndrome - metabolism; Metabolic Syndrome - pathology; Metabolome - drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Nuclear transport; Obesity - drug therapy; Obesity - metabolism; Oxazoles - chemistry; Oxazoles - therapeutic use; Phagocytosis; Pharmacology; Stress, Physiological - drug effects; TOR protein; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03939-w

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.