Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. 3122 85

Autophagy insufficiency due to aging, high-fat injury or genetic predisposition could be a factor in the progression of metabolic syndrome and diabetes. On the other hand, autophagy enhancement may have beneficial metabolic impact on in vivo metabolism of obese subjects. To identify novel, autophagy enhancer small molecules, we screened a chemical library using a Renilla-LC3-based luciferase assay [Lim et al. Nat Commun 9:1438]. Of the >7000 tested substances, one chemical compound, termed MSL (4-(4-fluorophenyl)sulfonyl-5-methylthio-2-phenyloxazole), (i) enhanced autophagic activity through Tfeb activation, (ii) expedited lipid clearance, probably through lipophagy, and (iii) reduced inflammasome activation through amelioration of mitochondrial dysfunction both in vitro and in vivo, leading to improved metabolic profile of mice with genetic or diet-induced obesity.
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PMID:Amelioration of obesity-induced diabetes by a novel autophagy enhancer. 2965 Sep 65