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

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• 作者：Mario Arciello ; Alessia Longo ; Carmela Viscomi ; Concetta Capo…
• 关键词：P53 ; Copper ; Metal homeostasis ; Fatty acid ; Hepatocyte
• 刊名：Biometals
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：28
• 期：6
• 页码：1017-1029
• 全文大小：1,638 KB
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• 作者单位：Mario Arciello (1) (2)
  Alessia Longo (2)
  Carmela Viscomi (2)
  Concetta Capo (3)
  Antonio Angeloni (1)
  Luisa Rossi (3)
  Clara Balsano (2)
  
  1. Department of Internal Medicine and Medical Specialties, 鈥淪apienza鈥?University of Rome, viale del Policlinico 155, 00161, Rome, Italy
  2. Laboratory of Molecular Virology and Oncology, Francesco Balsano Foundation, Rome, Italy
  3. Department of Biology, University of Rome 鈥淭or Vergata鈥? Rome, Italy
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciences
  Biochemistry
  Physical Chemistry
  
• 出版者：Springer Netherlands
• ISSN：1572-8773

文摘

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. Keywords P53 Copper Metal homeostasis Fatty acid Hepatocyte