期刊
DIABETOLOGIA
卷 59, 期 6, 页码 1276-1286出版社
SPRINGER
DOI: 10.1007/s00125-016-3912-9
关键词
Alternative binding site; Bavachinin; Canonical ligand-binding pocket; Carbohydrate metabolism; Lipid metabolism; Pan-PPAR agonist; Synergistic effects
资金
- National Natural Science Fund [81172951]
- Eastern Scholar Tracking Program of Shanghai Municipal Education Commission [2012-90]
- 'Xinlin' Scholars and Shanghai E-Research Institute of Bioactive Constituent in TCM Plan
Aims/hypothesis Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. Methods Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. Results BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-gamma agonists, and fibrates, which are PPAR-alpha agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-gamma agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. Conclusions/interpretation This is the first report of a synergistic glucose-and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-gamma or -alpha. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
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