18β-Glycyrrhetinic acid acts through hepatocyte nuclear factor 4 alpha to modulate lipid and carbohydrate metabolism

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) regulates the expression of essential genes involved in very-low-density lipoprotein (VLDL) homeostasis and gluconeogenesis. 18 beta-Glycyrrhetinic acid acts through hepatocyte nuclear factor 4 alpha to modulate lipid and carbohydrate metabolism-glycyrrhetinic acid (GA) is an active ingredient of Glycyrrhiza uralensis an herbal medicine used for treating liver aliments. In this study, we established that GA functions as a partial antagonist of HNF4 alpha through HNF4 alpha-driven reporter luciferase assay and coimmunoprecipitation experiments with co-activator PGC1 alpha. By virtual docking and site-directed mutagenesis analysis, we confirmed that serine 190 and arginine 235 of HNF4 alpha are both essential for GA to exert its antagonistic action on HNF4 alpha. Importantly, GA suppressed the expression of HNF4 alpha target genes such as apolipoprotein B (ApoB), microsomal triglyceride transfer protein (MTP) and phospholipase A(2) G12B (PLA2G12B) modulating hepatic VLDL secretion in mice fed on a high fat diet. In addition, GA also suppressed gluconeogenesis and ameliorated glucose intolerance via down-regulating the expression of HNF4 alpha target genes glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pepck). Furthermore, GA significantly lowered blood glucose and improved insulin resistance in db/db mice. In all, we established that GA acts as a partial HNF4 alpha antagonist modulating lipid and carbohydrate metabolism.