Direct imaging of the disruption of hepatitis C virus replication complexes by inhibitors of lipid metabolism

Abstract Here we have simultaneously characterized the influence of inhibitors of peroxisome proliferator-activated receptor α (PPARα) and the mevalonate pathway on hepatocyte lipid metabolism and the subcellular localization of hepatitis C virus (HCV) RNA using two-photon fluorescence (TPF) and coh...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2009-11, Vol.394 (1), p.130-142
Main Authors: Lyn, Rodney K, Kennedy, David C, Sagan, Selena M, Blais, David R, Rouleau, Yanouchka, Pegoraro, Adrian F, Xie, X. Sunney, Stolow, Albert, Pezacki, John Paul
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
CARS imaging
Cell Line
CHOLESTEROL
DIGESTIVE SYSTEM DISEASES
DISEASES
ESTERS
HCV
Hepacivirus - drug effects
Hepacivirus - physiology
HEPATITIS
Hepatitis C virus
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - virology
Humans
HYDROXY COMPOUNDS
Infectious Disease
INHIBITION
Lipid Metabolism - drug effects
LIPIDS
Lovastatin
MEMBRANE PROTEINS
MICROORGANISMS
MICROSCOPY
Microscopy, Fluorescence
NUCLEIC ACIDS
ORGANIC COMPOUNDS
PARASITES
PPAR alpha - antagonists & inhibitors
PPARalpha
PROTEINS
RAMAN EFFECT
RECEPTORS
RNA
RNA, Viral - metabolism
Spectrum Analysis, Raman
STEROIDS
STEROLS
TRIGLYCERIDES
Viral replication
Virus Replication - drug effects
VIRUSES
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Summary:Abstract Here we have simultaneously characterized the influence of inhibitors of peroxisome proliferator-activated receptor α (PPARα) and the mevalonate pathway on hepatocyte lipid metabolism and the subcellular localization of hepatitis C virus (HCV) RNA using two-photon fluorescence (TPF) and coherent anti-Stokes Raman scattering (CARS) microscopy. Using this approach, we demonstrate that modulators of PPARα signaling rapidly cause the dispersion of HCV RNA from replication sites and simultaneously induce lipid storage and increases in lipid droplet size. We demonstrate that reductions in the levels of cholesterol resulting from inhibition of the mevalonate pathway upregulates triglyceride levels. We also show that the rate of dispersion of HCV RNA is very rapid when using a PPARα antagonist. This occurs with a faster rate to that of direct inhibition of 3-hydroxy-3-methyglutaryl CoA reductase (HMG-CoA reductase) using lovastatin in living cells, demonstrating the potential therapeutic value of modulating host cell pathways as part of a strategy to eliminate chronic HCV infection.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2009.08.022