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Core domain mutant Y220C of p53 protein has a key role in copper homeostasis in case of free fatty acids overload

机译：p53蛋白的核心域突变体Y220C在游离脂肪酸超载的情况下对铜稳态具有关键作用

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Nonalcoholic fatty liver disease (NAFLD) is a pathology that includes a wide variety of clinical conditions ranging from simple steatosis to end-stage liver diseases. Despite the huge amount of researches, the molecular basis of NAFLD are still not fully understood. Recently, it was suggested a role for p53 in NAFLD pathogenesis. Among its targets there is Synthesis of Cytochrome c Oxidase 2 (SCO2), a copper chaperone, involved in both aerobic respiration and metal cellular excretion. Copper seems to play a role in NAFLD. It was demonstrated a low hepatic copper content in NAFLD patients, which correlates with metabolic syndrome parameters. Copper homeostasis deregulation, in fact, seems to be related to lipid metabolism alteration and insulin resistance. Here we provide evidence on the role of p53 in the modulation of copper homeostasis, in an experimental model of NAFLD. We used two different hepatoma cell lines, HepG2 and Huh 7.5.1, characterized by the presence of wt p53 and its Y220C mutant, respectively, treated with a free fatty acids (FFAs) solution. Interestingly, p53 activation correlated with the intracellular copper level maintenance. We demonstrated that, in hepatoma cell lines, core domain mutant Y220C of p53 affects the modulation of SCO2 and Copper transporter 1 (CTR1), influencing, in this way, intracellular copper homeostasis in presence of FFAs accumulation, and that the 220 residue of the protein is crucial for such control. The role of p53 we highlighted may have deep implications in clinical conditions where copper homeostasis is deregulated.
机译：非酒精性脂肪肝疾病（NAFLD）是一种包括从单纯脂肪变性到终末期肝病在内的多种临床疾病的病理学。尽管进行了大量的研究，但NAFLD的分子基础仍不完全清楚。最近，有人提出p53在NAFLD发病机理中的作用。其目标之一是细胞色素c氧化酶2（SCO2）的合成，一种铜伴侣，参与有氧呼吸和金属细胞排泄。铜似乎在NAFLD中起作用。事实证明，NAFLD患者肝铜含量低，这与代谢综合征参数有关。实际上，铜稳态失调似乎与脂质代谢改变和胰岛素抵抗有关。在这里，我们提供了在NAFLD实验模型中p53在铜稳态调节中的作用的证据。我们使用了两种不同的肝癌细胞系HepG2和Huh 7.5.1，其特征分别是存在wt p53及其Y220C突变体，并用游离脂肪酸（FFA）溶液处理过。有趣的是，p53激活与细胞内铜水平维持相关。我们证明，在肝癌细胞系中，p53的核心结构域突变体Y220C影响SCO2和铜转运蛋白1（CTR1）的调节，以这种方式影响存在FFA积累的细胞内铜稳态，并且铜的220个残基蛋白质对于这种控制至关重要。我们强调的p53的作用可能对铜稳态失去调节的临床状况产生深远的影响。

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