Ferritin Heavy Chain Is the Host Factor Responsible for HCV-Induced Inhibition of apoB-100 Production and Is Required for Efficient Viral Infection

Abstract

Hepatic fat export occurs by apolipoprotein B-100-containing lipoprotein production, whereas impaired production leads to liver steatosis. Hepatitis C virus (HCV) infection is associated to dysregulation of apoB-100 secretion and steatosis; however, the molecular mechanism by which HCV affects the apoB-100 secretion is not understood. Here, combining quantitative proteomics and computational biology, we propose ferritin heavy chain (Fth) as being the cellular determinant of apoB-100 production inhibition. By means of molecular analyses, we found that HCV nonstructural proteins and NS5A appear to be sufficient for inducing Fth up-regulation. Fth in turn was found to inhibit apoB-100 secretion leading to increased intracellular degradation via proteasome. Notably, intracellular Fth down-regulation by siRNA restores apoB-100 secretion. The inverse correlation between ferritin and plasma apoB-100 concentrations was also found in JFH-1 HCV cell culture systems (HCVcc) and HCV-infected patients. Finally, Fth expression was found to be required for robust HCV infection. These observations provide a further molecular explanation for the onset of liver steatosis and allow for hypothesizing on new therapeutic and antiviral strategies.

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…This could be rescued by FtH downregulation with specific siRNA. Interestingly, the reduction in FtH content was also associated with a less robust viral infection, thus indicating that FtH may be a host factor required for HCV infection (Mancone et al 2012). On the basis of the possible role of iron in the development of neurodegenerative processes, it is of particular interest a recent report showing that FtL can interact with Pen-2, a subunit of the multiprotein complex associated with the -secretase activity, involved in the processing of the amyloid precursor protein (Li et al 2013).The interaction has been found by the yeast two hybrid system and co-immunoprecipitation of the two proteins in cells overexpressing them.…”

Hepatitis C Virus, Cholesterol and Lipoproteins — Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

“…Indeed, the rate-limiting enzyme of VLDL production, microsomal triglyceride transfer protein (MTP), is transcriptionally repressed by HCV gene expression both in vitro [43], and in vivo [44], and associates with steatosis [44]. Recent studies suggest that the virus-induced dysregulation of apoB-100 secretion is mediated by increased ferritin heavy chain levels [45]. Indeed, an inverse correlation between ferritin and secreted apoB-100 concentrations is found both in JFH-1 HCVcc and HCV-infected patients, indicating a possible explanation for the onset of virus-induced liver steatosis [45].…”

“…Recent studies suggest that the virus-induced dysregulation of apoB-100 secretion is mediated by increased ferritin heavy chain levels [45]. Indeed, an inverse correlation between ferritin and secreted apoB-100 concentrations is found both in JFH-1 HCVcc and HCV-infected patients, indicating a possible explanation for the onset of virus-induced liver steatosis [45]. Steatosis is not only caused by HCV, but is also linked to pathogenesis and enhanced disease progression.…”

Data on the effects of low iron diet on serum lipid profile in HCV transgenic mouse model

“…In particular, studies on HCV (hepatitis-C-virus) transgenic mice fed an excess-iron diet demonstrated that hepatic iron overload exacerbates the imbalance of lipid metabolism by both lipogenesis activation and reduced oxidation activity of fatty acids [1], [2]. Moreover, HCV-induced iron accumulation contributes to liver steatosis by the inhibition of β-lipoproteins mediated fat export, thus leading hypobetalipoproteinemia [3], [4]. In this study, male B6HCV-transgenic mice [5] expressing the HCV polyprotein were fed a low-iron diet or a control diet for thirty days.…”