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.
| Original language | English |
|---|---|
| Pages (from-to) | 2786-2797 |
| Number of pages | 12 |
| Journal | Journal of Proteome Research |
| Volume | 11 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 4 2012 |
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Keywords
- HCV infection
- hypobetalipoproteinemia
- iron metabolism
- liver steatosis
ASJC Scopus subject areas
- Biochemistry
- Chemistry(all)
Cite this
Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection. / Mancone, Carmine; Montaldo, Claudia; Santangelo, Laura; Di Giacomo, Cristina; Costa, Viviana; Amicone, Laura; Ippolito, Giuseppe; Pucillo, Leopoldo Paolo; Alonzi, Tonino; Tripodi, Marco.
In: Journal of Proteome Research, Vol. 11, No. 5, 04.05.2012, p. 2786-2797.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ferritin heavy chain is the host factor responsible for HCV-induced inhibition of apoB-100 production and is required for efficient viral infection
AU - Mancone, Carmine
AU - Montaldo, Claudia
AU - Santangelo, Laura
AU - Di Giacomo, Cristina
AU - Costa, Viviana
AU - Amicone, Laura
AU - Ippolito, Giuseppe
AU - Pucillo, Leopoldo Paolo
AU - Alonzi, Tonino
AU - Tripodi, Marco
PY - 2012/5/4
Y1 - 2012/5/4
N2 - 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.
AB - 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.
KW - HCV infection
KW - hypobetalipoproteinemia
KW - iron metabolism
KW - liver steatosis
UR - http://www.scopus.com/inward/record.url?scp=84860605911&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860605911&partnerID=8YFLogxK
U2 - 10.1021/pr201128s
DO - 10.1021/pr201128s
M3 - Article
C2 - 22443280
AN - SCOPUS:84860605911
VL - 11
SP - 2786
EP - 2797
JO - Journal of Proteome Research
JF - Journal of Proteome Research
SN - 1535-3893
IS - 5
ER -