Peroxisome proliferator-activated receptor alpha antagonism inhibits hepatitis C virus replication.
Hepatitis C virus (HCV) is a global health problem and a leading cause of liver disease. Here, we demonstrate that the replication of HCV replicon RNA in Huh-7 cells is inhibited by a peroxisome proliferator-activated receptor (PPAR) antagonist, 2-chloro-5-nitro-N-(pyridyl)benzamide (BA). Downregulation of PPARgamma with RNA interference approaches had no effect on HCV replication in Huh-7 cells, whereas PPARalpha downregulation inhibited HCV replication. Fluorescence and coherent anti-Stokes Raman scattering (CARS) microscopy demonstrate a clear buildup of lipids upon treatment with BA. These observations are consistent with the misregulation of lipid metabolism, phospholipid secretion, cholesterol catabolism, and triglyceride clearance events associated with the inhibition of PPARalpha. The inhibition of HCV replication by BA may result from disrupting lipidation of host proteins associated with the HCV replication complex or, more generally, by disrupting the membranous web where HCV replicates.
Rakic
Bojana
B
The Steacie Institute for Molecular Sciences, The National Research Council of Canada, Ottawa, Ontario.
Sagan
Selena M
SM
Noestheden
Matthew
M
Bélanger
Sylvie
S
Nan
Xiaolin
X
Evans
Conor L
CL
Xie
X Sunney
XS
Pezacki
John Paul
JP
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015967:Gene Expression Regulation, Viral / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D015394:Molecular Structure; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
C509555:2-chloro-5-nitro-N-(pyridyl)benzamide; D001549:Benzamides; D008055:Lipids; D047493:PPAR alpha; D034741:RNA, Small Interfering