孕烷 X 受体被其天然配体银杏内酯 A 激活可改善肝硬化中紧密连接蛋白的表达并减轻细菌易位。
Pregnane X receptor activation by its natural ligand Ginkgolide-A improves tight junction proteins expression and attenuates bacterial translocation in cirrhosis.
机构信息
Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.
Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India.
出版信息
Chem Biol Interact. 2020 Jan 5;315:108891. doi: 10.1016/j.cbi.2019.108891. Epub 2019 Nov 4.
BACKGROUND AND AIMS
Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor expressed ubiquitously along gut-liver-axis. Inflammatory bowel disorders have been reported to implicate PXR in maintaining tight junction (TJ) integrity and countering inflammation. However, the hepatoprotective role of PXR activation in soothing bacterial translocation in liver cirrhosis has not been explored. Ginkgolide A (GA), a terpene trilactone from Ginkgo Biloba extract, is a natural ligand of rodent and human PXR. This study aims to investigate the effect of GA in activating PXR and improving associated tight junction integrity and reducing bacterial translocation in gut-liver axis of CCl induced cirrhosis model.
METHODS
Swiss albino mice were administered with CCl (0.5 ml/kg body weight, i.p) in corn oil for 12 weeks at an interval of two times a week. Following ascites induction, mice were randomized & administered 100 mg/kg body weight of GA through oral gavage for 2 weeks. At termination, blood, gut and liver tissues were collected for biochemical and molecular studies.
RESULTS
When compared to naïve mice, protein expression of hepatic and small intestinal PXR, CYP3A, ZO-1 and occludin were found to be significantly (p < 0.01) decreased in CCl induced cirrhotic mice. Treatment with GA to cirrhotic mice significantly (p < 0.05) induced the expression of both hepatic and small intestinal PXR, CYP3A, ZO-1 and Occludin. Furthermore, increased (p < 0.01) hepatic and small intestinal NFκB was observed in CCl induced cirrhotic mice that was significantly (p < 0.05) lowered following GA treatment. Over expression of TLR4/MyD88/NFκB axis and its downstream pro-inflammatory mediators TNF-α, IL6 and IFN-γ were observed in CCl induced mice, and these indices were abrogated significantly after GA treatment. Furthermore, significantly increased plasma levels of bacterial translocation markers LBP and procalcitonin were found in CCl mice, which were reduced significantly (p < 0.05 & p < 0.0001) after GA treatment.
CONCLUSION
In conclusion, our data supports the hypothesis that, GA treatment to CCl induced cirrhotic mice, activated hepatic and small intestinal PXR and diminished inflammation, thereby improving tight junction integrity and attenuating bacterial translocation.
背景和目的
孕烷 X 受体 (PXR) 是一种配体激活的转录因子和核受体，广泛表达于肠-肝轴。炎症性肠病已被报道涉及 PXR 在维持紧密连接 (TJ) 完整性和对抗炎症方面的作用。然而，PXR 激活在缓解肝硬化中细菌易位的肝保护作用尚未得到探索。银杏内酯 A (GA) 是银杏提取物中的一种三萜内酯，是啮齿动物和人类 PXR 的天然配体。本研究旨在探讨 GA 激活 PXR 对改善相关紧密连接完整性和减少 CCl 诱导的肝硬化模型中肠道-肝脏轴细菌易位的作用。
方法
瑞士白化小鼠用玉米油中的 CCl（0.5ml/kg 体重，腹腔内）每周两次给药 12 周。腹水诱导后，将小鼠随机分组并通过口服灌胃给予 100mg/kg 体重的 GA 持续 2 周。在终止时，收集血液、肠道和肝脏组织进行生化和分子研究。
结果
与未处理的小鼠相比，CCl 诱导的肝硬化小鼠的肝和小肠 PXR、CYP3A、ZO-1 和 occludin 的蛋白表达显著降低（p<0.01）。GA 处理肝硬化小鼠显著诱导肝和小肠 PXR、CYP3A、ZO-1 和 Occludin 的表达（p<0.05）。此外，在 CCl 诱导的肝硬化小鼠中观察到肝和小肠 NFκB 增加（p<0.01），而 GA 处理后明显降低（p<0.05）。在 CCl 诱导的小鼠中观察到 TLR4/MyD88/NFκB 轴及其下游促炎介质 TNF-α、IL6 和 IFN-γ的过度表达，GA 处理后这些指标明显降低。此外，在 CCl 小鼠中发现细菌易位标志物 LBP 和降钙素原的血浆水平显著升高（p<0.05 和 p<0.0001），而 GA 处理后显著降低（p<0.05 和 p<0.0001）。
结论
总之，我们的数据支持这样的假设，即 GA 处理 CCl 诱导的肝硬化小鼠可激活肝和小肠 PXR，减少炎症，从而改善紧密连接完整性并减轻细菌易位。
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