Endocrine Abstracts

Glycyrrhizin (GL) is a major bioactive triterpene glycoside of licorice root, a traditional Chinese herbal medicine. GL and primary metabolite 18β-glycyrrhetinic acid (GA) have been developed as anti-inflammatory and antiviral drugs for liver diseases in China and Japan. Hepatic VLDL secretory pathway is not only responsible for lipid homeostasis but also associated with viral particles assembly and secretion. Hepatocyte nuclear factor 4α (HNF4α) together with its downstream targets, namely, secreted phospholipase A2 G12B (PLA2G12B) and microsomal triglyceride transfer protein (MTP), regulate VLDL production and secretion. We hypothesized that GA may act through HNF4α to mediate some of its beneficial effects. We found that GA inhibits the transcriptional activity of HNF4α. Specifically, promoter reporter expression of PLA2G12B, MTP and ApoB activated by HNF4α are dose-dependently suppressed by GA. Through lipid droplet analysis in vitro, we further found that GA trended to elevate intracellular triglycerides levels in a dose dependent manner in Huh7 cells, indicating that VLDL production and secretion is suppressed. To investigate GA effects in vivo, we fed mice a high-fat diet for 19 weeks. These mice were then gavaged with GA 60 mg/kg (HFD-GA) or vehicle (HFD-ctrl) every day for 6 weeks. We found that VLDL secretion rate was lowered significantly by GA treatment in HFD mice compared to HFD-ctrl mice. Data from blood biochemistry analysis revealed that treatment with GA significantly reduced blood TG, TC, ALT, AST, and glucose. While hepatic TG and TC levels were increased by HFD feeding, GA blunted the amount elevated by HFD. Oil red O staining showed that the amount of fat droplets in HFD-GA hepatocytes were reduced noticeably compared to HFD-ctrl, indicating that GA treatment reduced neutral lipid accumulation in the liver. These evidence collectively suggested that GA acts as a modulator of HNF4α, not only alleviating hepatosteatosis but also reducing hepatic secretion of TG-rich VLDL implying an underlying mechanism for antiviral and hepatoprotective properties.