Abstract
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 PPARα and PPARγ, and enhanced their transcriptional activity; thus, sanguinarine was identified as a dual agonist of PPARα/γ. Similar to fenofibrate, sanguinarine upregulates the expression of PPARα-target genes in hepatocytes. Sanguinarine also modulates the expression of key PPARγ-target genes and promotes adipocyte differentiation, but with a lower adipogenic activity compared with rosiglitazone. We report the crystal structure of sanguinarine bound to PPARα, 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 PPARα. Further structural and functional studies uncover the molecular basis for the selectivity of sanguinarine toward PPARα/γ among all three PPARs. In summary, our study identifies a PPARα/γ dual agonist with a unique ligand-binding mode, and provides a promising and viable novel template for the design of dual-targeting PPARs ligands.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily involved in lipid and glucose metabolism, adipogenesis, and inflammation [1]
While considering the limitations of current PPAR agonists, we conducted a highthroughput AlphaScreenTM assay to search for novel ligands with distinct properties; this is widely used for detecting ligand-dependent interactions between nuclear receptors and their co-activators [21,22]
We found that the natural benzophenanthridine alkaloid sanguinarine, from the Enzo Natural Compound Library, greatly enhances the interaction between PPARα/γ–ligand-binding domain (LBD) and their co-activators (Figure S2)
Summary
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily involved in lipid and glucose metabolism, adipogenesis, and inflammation [1]. PPARs have been recognized as therapeutic targets for the treatment of diabetes, dyslipidemia, and nonalcoholic steatohepatitis, or fatty liver disease (NASH/NAFLD) [6]. While PPARα agonist fibrates are well-tolerated by most patients, some adverse effects have been reported, such as gastrointestinal disease, sleep disorder, renal disease, and liver dysfunction [7,8]. Thiazolidinediones (TZDs) have a high affinity and a full agonism to PPARγ. They improve insulin sensitivity and are used clinically for the treatment of T2DM, which is associated with various metabolic disorders, including obesity, hypertension, and dyslipidemia. A new drug design strategy for PPAR ligands, distinct from fibrates and TZDs, may yield more efficacious, PPAR-targeted drugs with fewer adverse effects
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