Sex-Related Differences of Lipid Metabolism Induced by Triptolide: The Possible Role of the LXRα/SREBP-1 Signaling Pathway

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.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

“…According to earlier reports, SREBP-1c plays a critical role in NASH progression and involves in tissue apoptosis [3,77], cell cycle control [78,79], transcription regulation [80], lipid metabolism [81,82], and many other life activities. All these are related to the development of NASH.…”

Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters

“…As a key regulator of detoxification and BA metabolism, Nrf2 induces a series of hepatic efflux transporters that aid in the elimination of potentially harmful endo- and xenobiotics ( Klaassen and Reisman, 2010 ; Zhang et al, 2017 ). Since TP-induced hepatotxicity is correlated with its hepatic exposure and BA accumulation which may lead to cholestatic symptoms ( Kong et al, 2015 ; Jiang et al, 2016 ; Yang et al, 2017 ), and licorice and its main constitutes have been proved to induce the expressions of an array of Nrf2 downstream transporters and inhibit chelostasis ( Wang X. et al, 2013 ; Gong et al, 2015 ), we measured changes in the expression of hepatic transporters after TP and ISL treatment. TP treatment reduced the expressions of MRP2 in vitro and in vivo , while ISL combined treatment reversed this effect.…”

“…Besides, since TP-induced hepatotoxicity is quantitatively correlated with the hepatic exposure to the parent drug, changes in pharmacokinetic profiles of TP may also influence its hepatotoxicity ( Kong et al, 2015 ), and CYP3A-mediated metabolism of TP is a detoxification pathway ( Xue et al, 2011 ). More recently, TP administration was found to increase the total bile acid (TBA) accumulation in rat livers ( Jiang et al, 2016 ; Yang et al, 2017 ), and activation of the BA receptor (FXR) ameliorates the TP-induced liver injuries ( Jin et al, 2015 ). Combined with the cholestatic symptoms of TP administration observed in clinics ( Xue et al, 2009 ), we speculate that besides the hepatic accumulation of TP, mechanisms involved in the change of endogenous BA profiles may as well contribute to TP-induced hepatotoxicity.…”

Activation of natural killer T cells contributes to triptolide-induced liver injury in mice

“…In TP-induced hepatotoxicity, sex-related differences in the toxicity of TP have received attention in recent years [42]. Female mice exhibit more severe toxicity than male mice [3]. Since sex is a fundamental biological variable that cannot be overlooked, only female mice were used in our toxicological research of TP.…”

“…Severe adverse reactions, however, especially hepatotoxicity, have greatly restricted its approval in the market. Although several published reports have demonstrated that TP causes liver injury by lipid peroxidation, stress responses, and hepatocyte necrosis [3,4], the underlying cellular mechanisms of TP-induced liver injury require more detailed investigations. Recently, it has been found that hepatocytes may not be the only target in drug-induced liver injury (DILI) [5].…”