Abstract
Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPARγ, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPARγ but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPARγ binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPARγ. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice. Moreover, chelerythrine improved insulin sensitivity by more potently blocking the phosphorylation of PPARγ by CDK5 compared to TZDs. These data fundamentally elucidate the mechanism by which chelerythrine retains the benefits of improving insulin sensitivity while reducing the adverse effects of TZDs, suggesting that the natural product chelerythrine is a very promising pharmacological agent by selectively targeting PPARγ for further development in the clinical treatment of insulin resistance.
Highlights
Been focused on another type of PPARγ ligands, selective PPAR modulators (SPPARMs)[15,16], which, unlike TZDs, do not exhibit full agonism
Chelerythrine is a major representative of quaternary benzophenanthridine alkaloids (QBAs) in C. majus and known to be a PKC inhibitor[25]
Our study indicates that chelerythrine is a PPARγ selective modulator with a cofactor profile that differs from rosiglitazone, which leads to its low transcriptional activity and partial agonism
Summary
Been focused on another type of PPARγ ligands, selective PPAR modulators (SPPARMs)[15,16], which, unlike TZDs, do not exhibit full agonism. Selective modulators of PPARγ have a more dynamic effect on the conformation of AF-2 than TZD full agonists[19], this conformational change results in differential cofactors profiling[20]. TZDs and SPPARMs such as MRL-24, SR1664 and UHC1 all inhibit the CDK5-mediated phosphorylation of PPARγ at serine 27321,22. We present comprehensive structural and functional evidence for identification chelerythrine as a selective PPARγ modulator that potently inhibited CDK5-mediated phosphorylation of PPARγ. We demonstrated that the unique binding of chelerythrine relative to TZDs resulted in a differential cofactor profile and partial agonism. Chelerythrine exhibits greater potency in regulating glucose homeostasis through inhibiting CDK5-mediated PPARγ phosphorylation than do TZDs and may represent a novel pharmacological agent in treating metabolic disease associated with T2DM
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