Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.
Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.
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DOI：
10.1016/j.celrep.2022.111498
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发表时间：
2022-10-18
期刊：
影响因子：
8.8
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Xie L;Yuan Y;Xu S;Lu S;Gu J;Wang Y;Wang Y;Zhang X;Chen S;Li J;Lu J;Sun H;Hu R;Piao H;Wang W;Wang C;Wang J;Li N;White MF;Han L;Jia W;Miao J;Liu J
铜缺乏已被发现与各种脂质代谢疾病有关，包括非酒精性脂肪肝病（NAFLD）。然而，决定铜缺乏与代谢疾病之间关联的机制仍然不清楚。在此，我们揭示了肝脏铜蓝蛋白 (Cp) 消融引起的铜恢复通过促进铜负载 SCO1-LKB1-AMPK 复合物的组装来增强脂质分解代谢。营养过剩介导的 Cp 升高会导致肝铜损失，而 Cp 消融可将铜含量恢复至正常水平，且不会引起可检测到的肝毒性，并可改善小鼠的 NAFLD。从机制上讲，即使在没有铜的情况下，SCO1 也会与 LKB1 发生组成性相互作用，并且负载铜的 SCO1 直接将 LKB1 与 AMPK 结合，从而激活 AMPK，从而促进线粒体生物发生和脂肪酸氧化。因此，本研究揭示了铜作为信号分子改善肝脏脂质分解代谢的机制，并表明靶向铜-SCO1-AMPK信号通路可通过调节AMPK活性来改善NAFLD的发展。谢等人。揭示铜蓝蛋白缺失可恢复 DIO 小鼠的肝铜，并通过增强线粒体生物发生和脂肪酸氧化来改善 NAFLD 的发展。从机制上讲，他们发现伴侣 SCO1 感知铜并通过形成 SCO1-LKB1-AMPK 复合物激活 AMPK。
Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms that dictate the association between copper deficiency and metabolic diseases remain obscure. Here, we reveal that copper restoration caused by hepatic ceruloplasmin (Cp) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1-LKB1-AMPK complex. Overnutrition-mediated Cp elevation results in hepatic copper loss, whereas Cp ablation restores copper content to the normal level without eliciting detectable hepatotoxicity and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation. Therefore, this study reveals a mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and it indicates that targeting copper-SCO1-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity. Xie et al. reveal that ceruloplasmin deletion restores hepatic copper in DIO mice and ameliorates NAFLD development via enhanced mitochondrial biogenesis and fatty acid oxidation. Mechanistically, they find that the chaperone SCO1 senses copper and activates AMPK by forming the SCO1-LKB1-AMPK complex.
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影响因子：
4.8
作者：
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通讯作者：
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通讯作者：
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