Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper.
Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper.
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DOI：
10.3389/fmolb.2022.863296
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发表时间：
2022
影响因子：
5
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中科院分区：
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铜是一种必需的金属微量营养素，具有从能量代谢到细胞信号转导等多种生物学作用。最近的研究表明，在啮齿类动物和细胞模型中，铜的调节都是通过脂肪积累来改变的，其表型与铜缺乏一致，包括铜转运蛋白ATP7B的表达上调。这项研究考察了暴露在过量脂肪酸中的肝细胞铜转运机制的变化。用饱和脂肪酸棕榈酸处理人肝癌细胞株HepG2，可诱导细胞摄取脂肪酸。伴侣蛋白、转运蛋白和螯合蛋白的变化表明，细胞中铜超载的初始状态随着时间的推移而转变为铜缺乏的状态。这种缺陷是由于铜被隔离到膜结合的铜蛋白、肝素和溶酶体单位中。这些变化与铜浓度的变化无关，支持在亚细胞水平上铜局部化的扰动。我们假设，脂肪积累触发了细胞内最初的铜错误区划，这是由于线粒体铜平衡的破坏，这导致了对胞质铜超载的动态平衡反应。这导致细胞激活铜输出和隔离机制，进而导致胞质铜缺乏的情况。综上所述，这项工作为之前在临床和啮齿动物模型中观察到的将铜缺乏状态与肥胖相关疾病联系起来的表型提供了分子洞察力。
Copper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated expression of the copper transporter, ATP7B. This study examines the changes in the copper trafficking mechanisms of liver cells exposed to excess fatty acids. Fatty acid uptake was induced in liver hepatocarcinoma cells, HepG2, by treatment with the saturated fatty acid, palmitic acid. Changes in chaperones, transporters, and chelators demonstrate an initial state of copper overload in the cell that over time shifts to a state of copper deficiency. This deficiency is due to sequestration of copper both into the membrane-bound copper protein, hephaestin, and lysosomal units. These changes are independent of changes in copper concentration, supporting perturbations in copper localization at the subcellular level. We hypothesize that fat accumulation triggers an initial copper miscompartmentalization within the cell, due to disruptions in mitochondrial copper balance, which induces a homeostatic response to cytosolic copper overload. This leads the cell to activate copper export and sequestering mechanisms that in turn induces a condition of cytosolic copper deficiency. Taken together, this work provides molecular insights into the previously observed phenotypes in clinical and rodent models linking copper-deficient states to obesity-associated disorders.