Severance Biomedical Science Institute, Seoul, Korea.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
Nat Commun. 2018 Apr 12;9(1):1438. 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.
自噬是细胞内稳态的关键调节者，其失调与多种疾病有关。在这里，我们展示了通过高通量筛选化学文库发现的一种新型自噬增强剂对代谢综合征的治疗效果。自噬增强剂可增加 LC3-I 向 LC3-II 的转化，而不抑制 mTOR。MSL，一种自噬增强剂，可激活钙调神经磷酸酶，并诱导转录因子 EB（TFEB）的去磷酸化/核易位，TFEB 是溶酶体生物发生和自噬基因表达的主要调节因子。MSL 可加速细胞内脂质清除，这可被 lalistat 2 或 Tfeb 敲除所逆转。其给药可改善 ob/ob 小鼠的代谢特征，并改善炎症小体的激活。一种具有增加的微粒体稳定性的化学修饰的 MSL 不仅可改善 ob/ob 小鼠的葡萄糖特征，还可改善饮食诱导肥胖的小鼠的葡萄糖特征。我们的数据表明，我们的新型自噬增强剂可能成为治疗糖尿病或代谢综合征伴脂质过载的新药候选物。
