A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats
A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats
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DOI：
10.1016/j.jcmgh.2018.12.005
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发表时间：
2019-01-01
影响因子：
7.2
通讯作者：
Zischka, Hans
中科院分区：
文献类型：
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作者：
Einer, Claudia;Leitzinger, Christin;Zischka, Hans
背景与目的：在Wilson病中，ATP 7 B突变损害铜向胆汁的排泄。肝铜蓄积可引起轻至中度慢性肝损伤甚至急性肝衰竭。这种异质性表型的病因仍然是个谜。肝脂肪变性是肝豆状核变性患者的常见表现，这表明铜稳态受损与肝脂肪变性有关。肝线粒体功能受到铜超载和脂肪变性的负面影响。因此，我们提出的问题，是否脂肪促进高热量的饮食通过放大线粒体damage.METHODS：控制Atp 7 b（+/-）和Wilson病Atp 7 b（-/-）大鼠喂养高热量饮食（HCD）或正常饮食中的肝损伤。铜螯合使用高亲和力的肽甲烷氧化菌素被用于在HCD喂养的Atp 7 b（-/-）大鼠测试线粒体铜damage.Results的治疗逆转：在与正常饮食相比，HCD喂养的Atp 7 b（-/-）大鼠导致在临床上明显的肝损伤的明显早期发作。在HCD喂养的Atp 7 b（-/-）大鼠中观察到线粒体铜积累强烈增加，与严重的肝损伤相关。线粒体出现大量的结构损伤，增加H2 O2的出现，以及功能失调的三磷酸腺苷的产生。肝细胞损伤可能是氧化应激的结果。减少线粒体铜甲烷氧化菌素显着降低线粒体损伤和改善肝损伤。结论：高热量的饮食严重的肝线粒体和肝细胞损伤的Wilson病大鼠，造成早期发病的疾病和增强的疾病进展。
BACKGROUND & AIMS: In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.METHODS: Control Atp7b(+/-) and Wilson disease Atp7b(-/-) rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b(-/-) rats to test for therapeutic reversal of mitochondrial copper damage.RESULTS: In comparison with a normal diet, HCD feeding of Atp7b(-/-) rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b(-/-) rats, correlating with severe liver injury. Mitochondria presentedwith massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage.CONCLUSIONS: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.