Structural and metabolic changes in Atp7b-/- mouse liver and potential for new interventions in Wilson's disease
Structural and metabolic changes in Atp7b-/- mouse liver and potential for new interventions in Wilson's disease
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DOI：
10.1111/nyas.12337
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Huster, Dominik
中科院分区：
文献类型：
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作者：
Huster, Dominik
肝豆状核变性（Wilson's disease，WD）是由ATP 7 B基因突变引起的一种肝、脑组织铜中毒性疾病。铜毒性的具体机制仍然知之甚少。小鼠模型揭示了肝WD的病理机制的新见解。在WD患者的肝脏和小鼠模型中观察到线粒体损伤;铜诱导线粒体膜脂质（特别是心磷脂）断裂，对线粒体完整性和功能都有有害影响。铜积累还诱导WD肝脏中的慢性炎症，随后是部分肝脏的再生和偶尔的肿瘤增殖。使用微阵列的基因表达研究有助于我们理解这些变化的分子基础。铜超载改变肝细胞中胆固醇的生物合成，导致肝脏和血清胆固醇降低。目前正在进行实验，以阐明铜和胆固醇代谢之间的联系。这些发现可能有助于开发特定的治疗方法来改善WD进展。
Wilson's disease (WD) is caused by ATP7B mutations and results in copper accumulation and toxicity in liver and brain tissues. The specific mechanisms underlying copper toxicity are still poorly understood. Mouse models have revealed new insights into pathomechanisms of hepatic WD. Mitochondrial damage is observed in livers of WD patients and in mouse models; copper induces fragmentation of mitochondrial membrane lipids, particularly cardiolipin, with deleterious effects on both mitochondrial integrity and function. Copper accumulation also induces chronic inflammation in WD livers, which is followed by regeneration in parts of the liver and occasionally neoplastic proliferation. Gene expression studies using microarrays have aided our understanding of the molecular basis of these changes. Copper overload alters cholesterol biosynthesis in hepatocytes resulting in reduced liver and serum cholesterol. Experiments are currently underway to elucidate the link between copper and cholesterol metabolism. These findings may facilitate the development of specific therapies to ameliorate WD progression.