Huster Dominik, Finegold Milton J, Morgan Clinton T, Burkhead Jason L, Nixon Randal, Vanderwerf Scott M, Gilliam Conrad T, Lutsenko Svetlana
Department of Biochemistry, Oregon Health & Science University, Portland, Oregon, USA.
Am J Pathol. 2006 Feb;168(2):423-34. doi: 10.2353/ajpath.2006.050312.
Wilson disease is a severe genetic disorder associated with intracellular copper overload. The affected gene, ATP7B, has been identified, but the molecular events leading to Wilson disease remain poorly understood. Here, we demonstrate that genetically engineered Atp7b-/- mice represent a valuable model for dissecting the disease mechanisms. These mice, like Wilson disease patients, have intracellular copper accumulation, low-serum oxidase activity, and increased copper excretion in urine. Their liver pathology developed in stages and was determined by the time of exposure to elevated copper rather than copper concentration per se. The disease progressed from mild necrosis and inflammation to extreme hepatocellular injury, nodular regeneration, and bile duct proliferation. Remarkably, all animals older than 9 months showed regeneration of large portions of the liver accompanied by the localized occurrence of cholangiocarcinoma arising from the proliferating bile ducts. The biochemical characterization of Atp7b-/- livers revealed copper accumulation in several cell compartments, particularly in the cytosol and nuclei. The increase in nuclear copper is accompanied by marked enlargement of the nuclei and enhanced DNA synthesis, with these changes occurring before pathology development. Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation.
威尔逊病是一种与细胞内铜过载相关的严重遗传性疾病。已确定了相关基因ATP7B，但导致威尔逊病的分子事件仍知之甚少。在此，我们证明基因工程改造的Atp7b-/-小鼠是剖析该病发病机制的宝贵模型。这些小鼠与威尔逊病患者一样，存在细胞内铜蓄积、血清氧化酶活性降低以及尿铜排泄增加的情况。它们的肝脏病理变化呈阶段性发展，取决于接触高铜的时间而非铜浓度本身。疾病从轻度坏死和炎症发展为严重的肝细胞损伤、结节状再生和胆管增生。值得注意的是，所有9个月以上的动物肝脏大部分出现再生，同时增生的胆管局部发生胆管癌。Atp7b-/-肝脏的生化特征显示，铜在多个细胞区室蓄积，尤其是在细胞质和细胞核中。核铜增加伴随着细胞核显著增大和DNA合成增强，这些变化在病理发展之前就已出现。我们的结果表明，铜对细胞遗传物质的早期影响对与Atp7b失活相关的病理变化有显著贡献。
