S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats.
S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats.
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DOI：
10.1152/ajpgi.00023.2017
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发表时间：
2018-02
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通讯作者：
S. Takemura;H. Azuma;Mayuko Osada-Oka;S. Kubo;T. Shibata;Y. Minamiyama
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文献类型：
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作者：
S. Takemura;H. Azuma;Mayuko Osada-Oka;S. Kubo;T. Shibata;Y. Minamiyama
S-烯丙基谷胱甘肽（SAG）是大蒜中二烯丙基硫醚（DAS）的代谢产物之一。DAS在动物模型中显示出对致癌作用的预防作用。然而，合成的SAG是否可以改善肝纤维化尚未研究。我们研究了SAG对慢性四氯化碳（CCl 4）给药的急性和慢性肝纤维化模型的潜在预防作用。SAG以剂量依赖性方式抑制CCl 4诱导的肝纤维化，并减少热休克蛋白47（HSP 47），胶原特异性伴侣和其他纤维化标志物。在纤维化消退模型中，给予CCl 4 9周或二甲基亚硝胺（DMN）6周后，SAG明显加速两种模型中的纤维溶解。在DMN处理的肝脏的消退阶段，SAG使枯否细胞（KCs）中的M2表型（甘露糖受体的表达）的比率正常化。与这些结果一致，经SAG处理的M2表型KC的培养上清液抑制原代培养活化的大鼠肝星状细胞（HSC）中胶原-α1（I）链（COL 1A 1）mRNA的表达。然而，SAG不直接抑制HSC活化。在CCl_4单次注射急性模型中，SAG剂量依赖性地抑制肝损伤，与抑制胆红素和ALT水平升高一致。这些结果表明，SAG可以通过调节过度活化和极化的KCs来改善纤维化和纤维溶解级联反应。SAG还可以作为目前临床治疗不可用的其他器官纤维化的预防和治疗剂。新&值得注意的是S-烯丙基谷胱甘肽（SAG）是二烯丙基硫醚的代谢产物，是大蒜的一种成分。SAG增加正常大鼠肝脏谷胱甘肽水平和GSH/GSSG比值。在慢性CCl 4给药导致肝纤维化之前或之后进行SAG治疗，可改善肝纤维化和消退。SAG降低热休克蛋白-47（HSP 47），一种胶原蛋白特异性伴侣蛋白，以及CCl 4处理的肝脏中的其他纤维化标志物。SAG处理的枯否细胞条件培养基也抑制原代培养的肝星状细胞中胶原-α1（I）链（COL 1A 1）mRNA的表达和其他标志物。
S-allyl-glutathione (SAG) is one of the metabolites of diallyl sulfide (DAS), a component of garlic. DAS has shown preventative effects on carcinogenesis in animal models. However, whether synthetic SAG can improve liver fibrosis has not been investigated. We examined the potential preventive effects of SAG on acute and chronic models of liver fibrosis by chronic carbon tetrachloride (CCl4) administration. SAG inhibited liver fibrogenesis induced by CCl4 in a dose-dependent manner and reduced heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers. In fibrosis regression models, after administration of either CCl4 for 9 wk or dimethyl nitrosamine (DMN) for 6 wk, SAG markedly accelerated fibrolysis in both models. In the regression stage of DMN-treated liver, SAG normalized the ratio of M2 phenotype (expression of mannose receptor) in Kupffer cells (KCs). Consistent with these results, the culture supernatants of SAG-treated M2-phenotype KCs inhibited collagen-α1(I) chain (COL1A1) mRNA expression in primary culture-activated rat hepatic stellate cells (HSCs). However, SAG did not directly inhibit HSC activation. In an acute model of CCl4 single injection, SAG inhibited hepatic injury dose dependently consistent with the inhibited the elevation of the bilirubin and ALT levels. These findings suggest that SAG could improve the fibrogenic and fibrolysis cascade via the regulation of excess activated and polarized KCs. SAG may also serve as a preventive and therapeutic agent in fibrosis of other organs for which current clinical therapy is unavailable. NEW & NOTEWORTHY S-allyl-glutathione (SAG) is a metabolite of diallyl sulfide, a component of garlic. SAG increased hepatic glutathione levels and GSH-to-GSSG ratio in normal rats. SAG treatment before or after liver fibrosis from chronic CCl4 administration improved liver fibrosis and regression. SAG decreased heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers in CCl4-treated livers. SAG-treated Kupffer cell conditioned medium also inhibited collagen-α1(I) chain (COL1A1) mRNA expression and other markers in primary culture hepatic stellate cells.