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.
Bibliographical noteFunding 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
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)