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

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.