Triterpenoids from Hibiscus sabdariffa L. with PPARδ/γ Dual Agonist Action: In Vivo, In Vitro and In Silico Studies

Abstract

<i>Hibiscus sabdariffa</i> is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors <i>δ</i> and <i>γ</i> may play a role in the actions of <i>H. sabdariffa.</i> These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from <i>H. sabdariffa</i> to identify compounds with peroxisome proliferator-activated receptor <i>δ</i> and peroxisome proliferator-activated receptor <i>γ</i> agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of <i>H. sabdariffa</i> and the dichloromethane extract of <i>H. sabdariffa</i> was performed. The dichloromethane extract of <i>H. sabdariffa</i> exhibited an antihyperglycemic effect. The dichloromethane extract of <i>H. sabdariffa</i> was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor <i>δ</i>, peroxisome proliferator-activated receptor <i>γ</i>, fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor <i>δ</i>/<i>γ</i> dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor <i>δ</i> and peroxisome proliferator-activated receptor <i>γ</i> expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were <i>α</i>-amyrin and lupeol. These molecules were subjected to molecular docking analysis. <i>α</i>-Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor <i>δ</i>, peroxisome proliferator-activated receptor <i>γ</i>, fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, <i>α</i>-amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, <i>α</i>-amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that <i>α</i>-amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor <i>δ</i>/<i>γ</i> dual agonist action.