title: Selective targeting of PPARγ by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency.
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.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Dezhou
authors.initials: D
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Scie-nces, Xiamen University, Fujian 361005, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D053119:Benzophenanthridines / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007333:Insulin Resistance; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D015430:Weight Gain
chemical_list: D053119:Benzophenanthridines; D001688:Biological Products; D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; C016299:chelerythrine; D051360:Cyclin-Dependent Kinase 5; D005947:Glucose