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

Abstract

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.

• Authors: Mario Arciello, Alessia Longo, Carmela Viscomi, Concetta Capo, Antonio Angeloni, Luisa Rossi, Clara Balsano
• Journal: Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine (Biometals) Vol. 28 Issue 6 Pg. 1017-29 (Dec 2015) ISSN: 1572-8773 [Electronic] Netherlands
• PMID: 26438057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cation Transport Proteins
• Copper Transporter 1
• Fatty Acids, Nonesterified
• Mitochondrial Proteins
• Molecular Chaperones
• SCO2 protein, human
• SLC31A1 protein, human
• Tumor Suppressor Protein p53
• Copper

Topics

• Carrier Proteins (genetics, metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Cell Line, Tumor
• Copper (metabolism)
• Copper Transporter 1
• Fatty Acids, Nonesterified (pharmacology)
• Gene Expression Regulation
• Hep G2 Cells
• Hepatocytes (cytology, drug effects, metabolism)
• Homeostasis
• Humans
• Mitochondrial Proteins (genetics, metabolism)
• Molecular Chaperones
• Mutation
• Protein Structure, Tertiary
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)