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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the most diffuse chronic liver disease in developed countries, where its prevalence ranges from 10 to 30 %
In hepatoma cell lines, core domain mutant Y220C of p53 affects the modulation of Synthesis of Cytochrome c Oxidase 2 (SCO2) and Copper transporter 1 (CTR1), influencing, in this way, intracellular copper homeostasis in presence of free fatty acids (FFAs) accumulation, and that the 220 residue of the protein is crucial for such control
The discovery that molecules implied in mechanisms like cell death and/or cell cycle control are involved in metabolic regulation, like p53, further widens the fields of investigation to understand the molecular basis of metabolic changes, and indicates how far we are from understanding them
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most diffuse chronic liver disease in developed countries, where its prevalence ranges from 10 to 30 %. NAFLD is frequently associated with the metabolic syndrome (MeS), of which it is considered the hepatic manifestation (Vanni et al 2010; Vetelainen et al 2007), as well as a pathogenic factor for its occurrence (Anstee et al 2013). This pathology refers to a wide variety of clinical conditions ranging from simple steatosis to the non-alcoholic steatohepatitis (NASH). The latter, in particular, might further progress to end-stage liver diseases until to hepatocarcinoma (HCC) (Schreuder et al 2008; Starley et al 2010). P53 protein, primarily known as a tumor suppressor, has been proposed as a new player in NAFLD pathogenesis, and growing evidences highlight its relevance as metabolic modulator (Panasiuk et al 2006; Derdak et al 2013)
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