Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that regulate lipid and glucose metabolism. PPARα mainly affects fatty acid metabolism, and its activation lowers lipid levels. PPARγ is involved in the regulation of adipogenesis, insulin sensitivity, energy balance, and lipid biosynthesis. We have previously reported that 4',6-dimethoxyisoflavone-7-O-β-D-glucopyranoside (wistin) can activate PPARγ. The purpose of the present study is to investigate the PPARα agonist activity of wistin. Using a luciferase reporter assay system of PPARα in monkey COS7 kidney cells, we showed that wistin could activate PPARα (P < 0.01 at 10 μg/mL) in a dose-dependent manner. Moreover, the addition of wistin upregulated the expression of PPARα (P < 0.01 at 10 μg/mL) and PPARα target genes including carnitine palmitoyltransferase 1a (P < 0.05 at 10 μg/mL), acyl-CoA oxidase (P < 0.01 at 10 μg/mL), acyl-CoA synthase (P < 0.05 at 10 μg/mL), PPARγ coactivator 1α (P < 0.05 at 10 μg/mL), uncoupling protein 2 (P < 0.05 at 1 μg/mL), and uncoupling protein 3 (P < 0.05 at 10 μg/mL), which are genes involved in lipid efflux and energy expenditure, in mouse primary hepatocytes. Furthermore, wistin inhibited cellular triglyceride accumulation in hepatocytes (P < 0.05 at 10 μg/mL) in a dose-dependent manner. These results indicate that wistin could suppress lipid accumulation through PPARα activation. The action of wistin on PPARα could be of interest for the amelioration of lipid metabolic disorders. To the best of our knowledge, wistin is the first reported isoflavonoid O-glycoside with PPARα agonist activity.
Keywords: Fatty acid oxidation; PPARα; PPARα agonist; Wistin.