Abstract
Triptolide, a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., exerts a unique bioactive spectrum of anti-inflammatory and anticancer activities. However, triptolide’s clinical applications are limited due to its severe toxicities. Fatty liver toxicity occurs in response to triptolide, and this toxic response significantly differs between males and females. This report investigated the pathogenesis underlying the sex-related differences in the dyslipidosis induced by triptolide in rats. Wistar rats were administered 0, 150, 300, or 450 μg triptolide/kg/day by gavage for 28 days. Ultrastructural examination revealed that more lipid droplets were present in female triptolide-treated rats than in male triptolide-treated rats. Furthermore, liver triglyceride, total bile acid and free fatty acid levels were significantly increased in female rats in the 300 and 450 μg/kg dose groups. The expression of liver X receptor α (LXRα) and its target genes, cholesterol 7α-hydroxylase (CYP7A1) and Sterol regulatory element-binding transcription factor 1(SREBP-1), increased following triptolide treatment in both male and female rats; however, the female rats were more sensitive to triptolide than the male rats. In addition, the expression of acetyl-CoA carboxylase 1(ACC1), a target gene of SREBP-1, increased in the female rats treated with 450 μg triptolide/kg/day, and ACC1 expression contributed to the sex-related differences in the triptolide-induced dysfunction of lipid metabolism. Our results demonstrate that the sex-related differences in LXR/SREBP-1-mediated regulation of gene expression in rats are responsible for the sex-related differences in lipid metabolism induced by triptolide, which likely underlie the sex-related differences in triptolide hepatotoxicity. This study will be important for predicting sex-related effects on the pharmacokinetics and toxicity of triptolide and for improving its safety.
Highlights
Triptolide is a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., a member of the Celastraceae family
To study the effects of triptolide treatment on lipid metabolism, we first evaluated the effects of triptolide on the serum chemistry parameters of the rats
Our results indicated that the serum total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) levels increased after triptolide treatment in both sexes and there were no statistically significant differences between male and female
Summary
Triptolide is a diterpenoid isolated from the plant Tripterygium wilfordii Hook. f., a member of the Celastraceae family. Triptolide is a diterpenoid isolated from the plant Tripterygium wilfordii Hook. F. possesses multiple pharmacological activities, including anti-inflammatory (Wang et al, 2014c), anti-fertility (Li et al, 2015), anti-cystogenesis, and anticancer activities (Li et al, 2015). Triptolide has a narrow therapeutic window, and its clinical applications are limited due to its severe toxicities, including hepatotoxicity (Li X. et al, 2014), nephrotoxicity (Sun et al, 2013), immunotoxicity (Wang et al, 2014a), and developmental and reproductive toxicities (Ni et al, 2008; Ma et al, 2015). Our previous toxicokinetic data indicated that the hepatotoxicity induced by triptolide correlates with its highest concentration in the liver (unpublished data). It is essential to elucidate the mechanism of TP-induced hepatotoxicity
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