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Picroside II protects against cholestatic liver injury possibly through activation of farnesoid X receptor.
Phytomedicine ( IF 6.7 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.phymed.2019.153153 Tingting Li 1 , Lijie Xu 2 , Rongyao Zheng 3 , Xinjie Wang 3 , Liwen Li 4 , Hui Ji 1 , Qinghua Hu 1
Phytomedicine ( IF 6.7 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.phymed.2019.153153 Tingting Li 1 , Lijie Xu 2 , Rongyao Zheng 3 , Xinjie Wang 3 , Liwen Li 4 , Hui Ji 1 , Qinghua Hu 1
Affiliation
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BACKGROUD
Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear.
PURPOSE
This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro.
METHODS
The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro.
RESULTS
Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II.
CONCLUSION
Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.
中文翻译：
Picroside II 可能通过激活法尼醇 X 受体来防止胆汁淤积性肝损伤。
背景 胆汁淤积，伴随着体内胆汁酸的积累，最终可能导致肝功能衰竭和肝硬化。胆甾醇紊乱的治疗方法有限。因此，需要开发合适的胆汁淤积治疗药物。Picroside II 是一种从 Picrorhiza scophulariiflora Pennell 中分离出来的生物活性成分，其抗胆汁淤积作用的机制尚未完全阐明，尤其是 Picroside II 通过核受体对胆汁酸稳态的作用仍不清楚。目的 本研究旨在研究苦苦苷 II 对 α-萘基异硫氰酸酯 (ANIT) 诱导的胆汁淤积性肝损伤的保肝作用，并阐明体内和体外机制。方法 ANIT 诱导的胆汁淤积小鼠模型使用或不使用苦苷酸 II 治疗。检查血清和胆汁生化指标，以及肝脏组织病理学变化。siRNA、双荧光素酶报告基因、定量实时 PCR 和蛋白质印迹分析用于证明法尼醇 X 受体 (FXR) 途径在体内和体外长黄酮苷 II 的抗胆汁淤积作用中。结果 Picroside II 通过肝功能受损和组织损伤对 ANIT 诱导的胆汁淤积发挥保肝作用。Picroside II 增加胆汁酸流出转运蛋白胆盐输出泵 (Bsep)、摄取转运蛋白牛磺胆酸钠协同转运多肽 (Ntcp) 和胆汁酸代谢酶硫酸盐转移酶 2a1 (Sult2a1) 和 UDP-葡萄糖醛酸转移酶 1a1 (Ugt1a1)，而降低胆汁酸合成酶胆固醇 7α-羟化酶 (Cyp7a1) 和氧甾醇 12α-羟化酶 (Cyp8b1)。此外，FXR 和靶基因 Bsep 的表达增加，而芳烃受体 (AhR)、孕烷 X 受体 (PXR)、过氧化物酶体增殖物激活受体α (PPARα) 及其相应的靶基因不受苦苷酸 II 的显着影响在胆汁淤积条件下。此外，在小鼠原代培养的肝细胞中，FXR 沉默消除了苦苷酸 II 对参与胆汁酸稳态的转运蛋白和酶的调节。在 HepG2 细胞中进行的双荧光素酶报告基因检测显示了苦苷酸 II 对 FXR 的激活。结论 我们的研究结果表明，picroside II 可能通过调节参与胆汁酸稳态的转运蛋白和酶的 FXR 激活对 ANIT 诱导的胆汁淤积发挥保护作用。Picroside II 可能是防治胆汁淤积性肝病的有效途径。
更新日期：2019-12-17
中文翻译：
Picroside II 可能通过激活法尼醇 X 受体来防止胆汁淤积性肝损伤。
背景 胆汁淤积，伴随着体内胆汁酸的积累，最终可能导致肝功能衰竭和肝硬化。胆甾醇紊乱的治疗方法有限。因此，需要开发合适的胆汁淤积治疗药物。Picroside II 是一种从 Picrorhiza scophulariiflora Pennell 中分离出来的生物活性成分，其抗胆汁淤积作用的机制尚未完全阐明，尤其是 Picroside II 通过核受体对胆汁酸稳态的作用仍不清楚。目的 本研究旨在研究苦苦苷 II 对 α-萘基异硫氰酸酯 (ANIT) 诱导的胆汁淤积性肝损伤的保肝作用，并阐明体内和体外机制。方法 ANIT 诱导的胆汁淤积小鼠模型使用或不使用苦苷酸 II 治疗。检查血清和胆汁生化指标，以及肝脏组织病理学变化。siRNA、双荧光素酶报告基因、定量实时 PCR 和蛋白质印迹分析用于证明法尼醇 X 受体 (FXR) 途径在体内和体外长黄酮苷 II 的抗胆汁淤积作用中。结果 Picroside II 通过肝功能受损和组织损伤对 ANIT 诱导的胆汁淤积发挥保肝作用。Picroside II 增加胆汁酸流出转运蛋白胆盐输出泵 (Bsep)、摄取转运蛋白牛磺胆酸钠协同转运多肽 (Ntcp) 和胆汁酸代谢酶硫酸盐转移酶 2a1 (Sult2a1) 和 UDP-葡萄糖醛酸转移酶 1a1 (Ugt1a1)，而降低胆汁酸合成酶胆固醇 7α-羟化酶 (Cyp7a1) 和氧甾醇 12α-羟化酶 (Cyp8b1)。此外，FXR 和靶基因 Bsep 的表达增加，而芳烃受体 (AhR)、孕烷 X 受体 (PXR)、过氧化物酶体增殖物激活受体α (PPARα) 及其相应的靶基因不受苦苷酸 II 的显着影响在胆汁淤积条件下。此外，在小鼠原代培养的肝细胞中，FXR 沉默消除了苦苷酸 II 对参与胆汁酸稳态的转运蛋白和酶的调节。在 HepG2 细胞中进行的双荧光素酶报告基因检测显示了苦苷酸 II 对 FXR 的激活。结论 我们的研究结果表明，picroside II 可能通过调节参与胆汁酸稳态的转运蛋白和酶的 FXR 激活对 ANIT 诱导的胆汁淤积发挥保护作用。Picroside II 可能是防治胆汁淤积性肝病的有效途径。
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