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

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42 Citations (Scopus)

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.

Original languageEnglish
Article number1438
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
The authors thank M. Jȁȁttelȁ for kind provision of pRLuc(C124A)-LC3(WT) and pRLuc(C124A)-LC3(G120A) constructs and J.S. Song for measurement of in vivo concentration of MSL or MSL-7. CRISPR/Cas9 Tfeb-knockout HeLa cells, Tfeb-GFP-transfectant HeLa cells, 3xFLAG-Tfeb WT/S142D mutant, Δcan/ΔCnA-H151Q, mRFP-GFP, and GCaMP3-ML1 plasmid are gifts from R. Youle, E. Jho, A. Ballabio, L. Scorrano, T. Yoshimori, and H. Xu, respectively. This study was supported by Global Research Laboratory Grant (K21004000003-12A0500-00310) and Bio&Medical Technology Development Program (NRF-2015M3A9B6073846). M-S Lee and HJ Kwon are the recipient of UNIST Fund (2014M3A9D8034459 to M-S Lee) and NRF grants (M.-S. Lee: 2015K2A2A6002060; H.J. Kwon: 2015K1A1A2028365 and 2015M3A9C4076321).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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