Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice.
Mice deficient in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase exhibit enhanced liver fibrosis and delayed recovery from fibrosis in carbon tetrachloride-treated mice.
复制标题
DOI：
10.1016/j.heliyon.2016.e00138
复制
发表时间：
2016-08
期刊：
影响因子：
4
通讯作者：
Habuchi O
中科院分区：
文献类型：
--
作者：
Habuchi H;Ushida T;Habuchi O
富含N-乙酰半乳糖胺4,6-二硫酸盐(GalNAc(4,6SO4))残基的软骨素/硫酸皮肤素(CS/DS)在小鼠肝脏中以核心蛋白聚糖和/或双糖链蛋白聚糖的形式存在，并且在N-乙酰半乳糖胺4-硫酸盐6-O-磺基转移酶(GalNAc4S-6ST)敲除(KO)中GalNAc(4,6SO4)残基完全消失老鼠。本研究的目的是探讨富含GalNAc(4,6SO4)残基的CS/DS是否参与肝纤维化的进展或消退。野生型 (WT) 和 GalNAc4S-6ST KO 小鼠用 CCl4 处理 5 周。停止CCl4给药后，比较WT和GalNAc4S-6ST KO小鼠的组织化学和生化变化以及与基质成分相关的基因的表达。停止 CCl4 给药 2 天后，通过天狼星红染色观察到 KO 小鼠的纤维化程度高于 WT 小鼠。 KO 小鼠的血清丙氨酸转氨酶活性高于 WT 小鼠。羟脯氨酸含量和天狼星红染色显示，KO 小鼠恢复阶段的肝纤维化修复似乎延迟。基质金属蛋白酶(MMP)-2、MMP-13和多功能蛋白聚糖的mRNA表达在停止CCl4给药后2天达到峰值，并且KO小鼠中的表达高于WT小鼠中的表达。 KO小鼠恢复期MMP-9的表达低于WT小鼠。我们的研究结果表明，GalNAc4S-6ST 的缺陷会导致含有 GalNAc(4,6SO4) 的 CS/DS 消失，似乎会导致四氯化碳处理小鼠的肝纤维化进展、纤维化恢复延迟以及蛋白聚糖和 MMP 表达的各种变化。
Chondroitin/dermatan sulfate (CS/DS) rich in N-acetylgalactosamine 4,6-bissulfate (GalNAc(4,6SO4)) residues is present as decorin and/or biglycan in mouse liver, and GalNAc(4,6SO4) residues disappeared completely in N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST) knockout (KO) mice. The aim of this study was to investigate whether CS/DS rich in GalNAc(4,6SO4) residues participate in the progression or resolution of liver fibrosis. Wild type (WT) and GalNAc4S-6ST KO mice were treated with CCl4 for 5 weeks. After discontinuation of CCl4 administration, histochemical and biochemical changes and expression of genes related to matrix components were compared between WT and GalNAc4S-6ST KO mice. On 2 days after cessation of CCl4 administration, higher fibrosis was observed in KO mice than in WT mice by Sirius Red staining. Serum alanine aminotransferase activity was higher in KO mice than in WT mice. Hydroxyproline contents and Sirius Red staining showed that repair of liver fibrosis in the recovery stages appeared to be delayed in KO mice. Expression of mRNA of matrix metalloproteinase (MMP)-2, MMP-13 and versican peaked at 2 days after cessation of CCl4 administration and was higher in KO mice than in WT mice. Expression of MMP-9 in the recovery stage was lower in KO mice than in WT mice. Our findings demonstrate that defect in GalNAc4S-6ST, which resulted in disappearance of CS/DS containing GalNAc(4,6SO4), appear to contribute to progression of liver fibrosis, delayed recovery from fibrosis, and various changes in the expression of proteoglycans and MMPs in carbon tetrachloride–treated mice.