Authors:
Wei Yang, Brian L. Hood , Sara L. Chadwick , Shufeng Liu , Simon C. Watkins , Guangxiang Luo , Thomas P. Conrads ,and Tianyi Wang
Summary:
Hepatitis C virus (HCV) is a major human pathogen that causes serious illness including acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Using a mass spectrometry-based proteomics approach, we have identified 175 proteins from a cell culture supernatant fraction containing HCV JFH1 virus, among which fatty acid synthase (FASN), the multifunctional enzyme catalyzing the de novo synthesis of fatty acids, was confirmed to be highly enriched. Subsequent studies showed that FASN expression increased in the human hepatoma cell line, Huh7 or its derivative, upon HCV infection. Blocking FASN activity by a pharmacological inhibitor C75 led to decreased HCV production. Reduction of FASN by RNA interference (RNAi) suppressed viral replication in both replicon and infection systems. Remarkably, FASN appeared to be selectively required for the expression of claudin-1 (CLDN1), a tight junction (TJ) protein that was recently identified as an entry co-receptor for HCV (1), but not for the expression of another HCV co-receptor, CD81. The decrease in CLDN1 expression resulting from FASN inhibition was accompanied by a decrease in transepithelial electric resistance (TER) of Huh7 cells, implying a reduction in the relative tightness of the cell monolayer. Consequently, the entry of HIV-HCV pseudotypes (HCVpp) was significantly inhibited in C75 treated Huh7 cells. Conclusion: As far as we know, this is the first line of evidence that demonstrates that HCV infection directly induces FASN expression, and thus suggests a possible mechanism by which HCV infection alters the cellular lipid profile and causes diseases such as steatosis.
Source:
Hepatology; Vol. 9999, Issue 999A, 07/09/08