Structural Basis for PPARs Activation by The Dual PPARα/γ Agonist Sanguinarine: A Unique Mode of Ligand Recognition

Peroxisome proliferator-activated receptors (PPARs) play crucial roles in glucose and lipid metabolism and inflammation. Sanguinarine is a natural product that is isolated from Sanguinaria Canadensis, a potential therapeutic agent for intervention in chronic diseases. In this study, biochemical and cell-based promoter-reporter gene assays revealed that sanguinarine activated both PPAR alpha and PPAR gamma, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPAR alpha/gamma. Similar to fenofibrate, sanguinarine upregulates the expression of PPAR alpha-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPAR gamma-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPAR alpha, which reveals a unique ligand-binding mode of sanguinarine, dissimilar to the classic Y-shaped binding pocket, which may represent a new pharmacophore that can be optimized for selectively targeting PPAR alpha. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPAR alpha/gamma among all three PPARs. In summary, our study identifies a PPAR alpha/gamma dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.

Automated summary

The study identified sanguinarine as a dual agonist of PPAR alpha and PPAR gamma, showing promising therapeutic potential in chronic diseases. It was found to upregulate PPAR alpha-target genes in hepatocytes and modulate key PPAR gamma-target genes to promote adipocyte differentiation. The unique ligand-binding mode of sanguinarine to PPAR alpha highlights its potential as a novel template for dual-targeting PPARs ligands.