Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production

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Hepatology. 2008 Jul 9. [Epub ahead of print]

Fatty acid synthase is up-regulated during hepatitis C virus infection and

regulates hepatitis C virus entry and production.

Yang W, Hood BL, Chadwick SL, Liu S, Watkins SC, Luo G, Conrads TP, Wang T.

Department of Infectious Diseases and Microbiology, University of Pittsburgh

Cancer Institute, University of Pittsburgh, Pittsburgh, PA.

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 the HCV genotype 2a

(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 C75, a pharmacological FASN inhibitor, led to decreased HCV

production. Reduction of FASN by RNA interference suppressed viral replication

in both replicon and infection systems. Remarkably, FASN appeared to be

selectively required for the expression of claudin-1, a tight junction protein

that was recently identified as an entry coreceptor for HCV, but not for the

expression of another HCV coreceptor, CD81. The decrease in Claudin-1 expression

resulting from FASN inhibition was accompanied by a decrease in transepithelial

electric resistance of Huh7 cells, implying a reduction in the relative

tightness of the cell monolayer. Consequently, the entry of human

immunodeficiency virus-HCV pseudotypes 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. (HEPATOLOGY

2008.).

PMID: 18830996 [PubMed - as supplied by publisher]