Ginkgolide B lowers body weight and ameliorates hepatic steatosis in high-fat diet-induced obese mice correlated with pregnane X receptor activation

Abstract

Ginkgolide B (GB) is a natural occurring terpene lactone and has pharmacological function in the cardiovascular system. In the screening of pregnane X receptor (PXR) ligands, we found that GB is a PXR agonist. In the present study, we investigated the effects of GB on metabolic disorders in high-fat (HF) diet-induced obesity (DIO) C57BL/6 mice. A reporter gene assay was used to analyze the effects of GB on human PXR (hPXR) transactivity. DIO mice were divided into three groups randomly, and were fed with HF alone, or HF mixed with 0.1% GB (w/w) or HF mixed with 0.025% obeticholic acid (OCA) for 7 weeks. Control lean group mice were fed with a normal diet (chow). Body weight was measured every other day. At the end of the treatment, the fasting blood glucose, glucose tolerance, serum lipid profile, liver lipid content and morphology of the liver of DIO mice were analyzed. The gene expression analysis was performed with a quantitative real-time PCR assay. The results showed that GB activated hPXR transactivity in a dose dependent manner, while GB did not change peroxisome proliferator-activated receptor (PPAR)α, PPARβ, PPARγ, liver X receptor (LXR)α, LXRβ and farnesyl X receptor (FXR) transactivities. GB treatment reduced body weight and serum triglyceride (TG) levels, and ameliorated hepatic steatosis in DIO mice. A mechanistic study showed that GB increased the mRNA expression of PXR target genes in the DIO mouse liver. Our study suggests that GB may reduce body weight, lower serum TG and improve lipid accumulation in the liver of DIO mice through the activation of PXR signaling.