Inactivating mutations in the copper transporter Atp7b result in Wilson's disease. The Atp7b -/- mouse develops hallmarks of Wilson's disease. The activity of several nuclear receptors decreased in Atp7b -/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b -/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography-mass spectrometry and correlated with transcriptomic data. Atp7b -/- mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, Atp7b -/- mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. Atp7b -/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b -/- mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b -/- mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b -/- mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in Atp7b -/- mice.

中文翻译：

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Atp7b-/-威尔逊氏病小鼠模型中的代谢异常。

铜转运蛋白Atp7b中的失活突变导致威尔逊氏病。Atp7b-/-小鼠具有威尔逊氏病的特征。在Atp7b-/-小鼠中，几种核受体的活性下降，而核受体对于维持代谢稳态至关重要。因此，我们预期Atp7b-/-小鼠会表现出饮食诱发的肥胖，脂肪肝和胰岛素抵抗的改变。10周饮食或西式饮食（40％大卡脂肪）后，测量葡萄糖和脂质稳态的参数。肝代谢产物通过液相色谱-质谱法测定并与转录组数据相关。与野生型（WT）同窝出生的对照组相比，喂食低脂饮食的Atp7b-/-小鼠体重随着时间的推移而增加，脂肪含量更低，并且对葡萄糖的耐受性更高。在西方饮食中，与WT对照相比，Atp7b-/-小鼠表现出降低的体重，肥胖和肝脂肪变性。饲喂两种饮食的Atp7b-/-小鼠比WT对照组的胰岛素敏感性更高；但是，禁食的Atp7b-/-小鼠在给药胰岛素后由于葡萄糖反调节反应受损而表现出低血糖症，这可通过减少肝脏葡萄糖的产生来证明。将基因表达与代谢组学分析相结合，我们观察到Atp7b-/-小鼠肝脏代谢谱的显着变化，包括糖酵解中间产物和三羧酸循环的成分增加。另外，相对于野生型对照，在Atp7b-/-小鼠中AMP激酶的活性磷酸化形式显着增加。