Alpha-1 antitrypsin z protein (PiZ) increases hepatic fibrosis in a murine model of Cholestasis
Alpha-1 antitrypsin z protein (PiZ) increases hepatic fibrosis in a murine model of Cholestasis
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DOI：
10.1002/hep.21832
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Brenner, David A.
中科院分区：
文献类型：
--
作者：
Mencin, Ali;Seki, Ekihiro;Brenner, David A.
α-1抗胰蛋白酶（α 1-AT）缺乏症是儿童肝脏疾病最常见的遗传原因。纯合子α 1-ATZ突变（PiZZ）导致10%的所有受影响患者的显著肝脏疾病。α 1-ATZ突变也可能导致其他肝脏疾病（如囊性纤维化、非酒精性脂肪肝和丙型肝炎）的肝损伤加重。虽然胆汁淤积性损伤常见于许多形式的肝脏疾病，但其对PiZZ表型的影响尚不清楚。为了阐明胆汁淤积和PiZZ表型的相互作用，我们对具有转基因α 1-ATZ突变的C57 BL/6小鼠和同窝对照进行胆管结扎（BDL）。通过天狼星红染色（P = 0.0003）和羟脯氨酸（P = 0.007）的定量，经历BDL的PiZ转基因小鼠比野生型小鼠在BDL后发展更多的肝纤维化。在PiZ BDL模型中还观察到更多的活化的肝星状细胞（HSC）和凋亡细胞。内质网（ER）应激标志物CHOP和GRP 78的定量真实的实时聚合酶链反应（PCR）分别为4倍和2倍，与野生型BDL小鼠相比，PiZ BDL小鼠上调（P = 0.02，P = 0.02）。通过末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）和切割的半胱天冬酶-3组织学染色，还注意到PiZ BDL小鼠中细胞凋亡增加。结论：PiZ转基因小鼠更易发生胆汁淤积性肝纤维化。因此，胆汁淤积可能导致α 1-AT缺乏症的纤维化增加，α 1-ATZ突变可能在并发胆汁淤积性肝病如囊性纤维化的患者中起修饰基因的作用。
Alpha-1 antitrypsin (alpha 1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous alpha 1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The alpha 1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic alpha 1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P = 0.0003) and hydroxyproline (P = 0.007) than wildtype mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P = 0.02, P = 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. Conclusion: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in alpha 1-AT deficiency, and the alpha 1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.