4',6-Dimethoxyisoflavone-7-O-beta-d-glucopyranoside (wistin) is a peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist in mouse hepatocytes

摘要

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that regulate lipid and glucose metabolism. PPAR alpha mainly affects fatty acid metabolism, and its activation lowers lipid levels. PPAR gamma is involved in the regulation of adipogenesis, insulin sensitivity, energy balance, and lipid biosynthesis. We have previously reported that 4',6-dimethoxyisoflavone-7-O-beta-d-glucopyranoside (wistin) can activate PPAR gamma. The purpose of the present study is to investigate the PPAR alpha agonist activity of wistin. Using a luciferase reporter assay system of PPAR alpha in monkey COS7 kidney cells, we showed that wistin could activate PPAR alpha (P 0.01 at 10 mu g/mL) in a dose-dependent manner. Moreover, the addition of wistin upregulated the expression of PPAR alpha (P 0.01 at 10 mu g/mL) and PPAR alpha target genes including carnitine palmitoyltransferase 1a (P 0.05 at 10 mu g/mL), acyl-CoA oxidase (P 0.01 at 10 mu g/mL), acyl-CoA synthase (P 0.05 at 10 mu g/mL), PPAR gamma coactivator 1 alpha (P 0.05 at 10 mu g/mL), uncoupling protein 2 (P 0.05 at 1 mu g/mL), and uncoupling protein 3 (P 0.05 at 10 mu g/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 mu g/mL) in a dose-dependent manner. These results indicate that wistin could suppress lipid accumulation through PPAR alpha activation. The action of wistin on PPAR alpha 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 PPAR alpha agonist activity.