Tissue transglutaminase does not affect fibrotic matrix stability or regression of liver fibrosis in mice.
Tissue transglutaminase does not affect fibrotic matrix stability or regression of liver fibrosis in mice.
复制标题
DOI：
10.1053/j.gastro.2011.01.040
复制
发表时间：
2011-05
期刊：
影响因子：
29.4
通讯作者：
Schuppan D
中科院分区：
文献类型：
--
作者：
Popov Y;Sverdlov DY;Sharma AK;Bhaskar KR;Li S;Freitag TL;Lee J;Dieterich W;Melino G;Schuppan D
尽管缺乏功能证据，但普遍存在的交联酶组织转谷氨酰胺酶 (TG2) 与肝纤维化中不可逆的胶原蛋白稳定有关。我们研究了 TG2 对肝纤维化基质稳定性的贡献，以及 TG2 缺陷小鼠的肝纤维化进展和消退。通过四氯化碳 (CCL4) 或硫代乙酰胺 (TAA) 在 TG2−/− 小鼠及其野生型同窝小鼠中诱导晚期肝纤维化，以研究纤维化进展及其自发消退长达 36 周。通过组织学和肝羟脯氨酸定量分析纤维化的模式和程度。通过逐步提取胶原蛋白来评估肝基质交联的动态变化。通过定量逆转录 PCR 测定 7 种转谷氨酰胺酶和纤维化相关基因的表达。纤维化时转谷氨酰胺酶活性增加，TG2 mRNA 水平与纤维化相关基因的表达相关。生化分析显示胶原蛋白逐渐稳定，高度交联的胃蛋白酶不溶部分增加了多达 6 倍 (26%)。在 TG2−/− 小鼠中，肝脏转谷氨酰胺酶活性显着降低，但长期施用 CCL4 或 TAA 会导致与野生型小鼠相当的肝纤维化程度和模式。在TG2−/−小鼠中，肝胶原组分的组成和纤维化相关转录物的水平没有变化，并且不促进纤维化逆转。 TG2 和转谷氨酰胺酶活性在肝纤维化进展过程中上调，但不会促进纤维形成或胶原基质的稳定。 TG2缺失不会促进肝纤维化的消退。不依赖TG2的胶原交联是进展性肝纤维化的显着特征，也是肝纤维化的重要治疗靶点。
The ubiquitous crosslinking enzyme tissue transglutaminase (TG2) has been implicated in irreversible collagen stabilization in liver fibrosis, although functional evidence is lacking. We studied the contribution of TG2 to hepatic fibrotic matrix stability, as well as liver fibrosis progression and regression in TG2-deficient mice. Advanced liver fibrosis was induced by carbon tetrachloride (CCL4) or thioacetamide (TAA) in TG2−/− mice and their wild-type littermates to study fibrosis progression and its spontaneous regression for up to 36 weeks. Pattern and extent of fibrosis were analyzed by histology and hepatic hydroxyproline quantification. Dynamic changes in hepatic matrix crosslinking were assessed by stepwise collagen extraction. Expression of 7 transglutaminases and of fibrosis-related genes were determined by quantitative reverse transcription PCR. Transglutaminase activity was increased in fibrosis, and level of TG2 mRNA correlated with expression of fibrosis-related genes. Biochemical analysis revealed progressive collagen stabilization, with an up to 6-fold increase in the highly crosslinked, pepsin-insoluble fraction (26%). In TG2−/− mice, hepatic transglutaminase activity was significantly decreased, but chronic administration of CCL4 or TAA led to a comparable extent and pattern of liver fibrosis, as in wild-type mice. In TG2−/− mice, the composition of hepatic collagen fractions and levels of fibrosis-related transcripts were unchanged, and fibrosis reversal was not facilitated. TG2 and transglutaminase activity are upregulated during hepatic fibrosis progression, but do not contribute to fibrogenesis or stabilization of the collagen matrix. TG2 deletion does not promote regression of liver fibrosis. TG2-independent collagen crosslinking is a remarkable feature of progressing hepatic fibrosis and represents an important therapeutic target for liver fibrosis.
登录
查看更多内容
影响因子：
29.4
作者：
Issa, R;Zhou, XY;Iredale, JP
通讯作者：
Iredale, JP
影响因子：
4.8
作者：
Popov, Yury;Patsenker, Eleonora;Schuppan, Detlef
通讯作者：
Schuppan, Detlef
影响因子：
6
作者：
Nardacci, R;Iacono, OL;Piacentini, M
通讯作者：
Piacentini, M
影响因子：
25.7
作者：
Popov, Y;Patsenker, E;Schuppan, D
通讯作者：
Schuppan, D
影响因子：
24.5
作者：
Dieterich, W;Trapp, D;Schuppan, D
通讯作者：
Schuppan, D