Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism

Background & Aims Hepatitis C virus (HCV) infection affects 3% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50% of the patients, poorly tolerated, and associated with significant side effects and viral resistan...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of hepatology 2011-11, Vol.55 (5), p.963-971
Main Authors:	Goldwasser, Jonathan, Cohen, Pazit Y, Lin, Wenyu, Kitsberg, Danny, Balaguer, Patrick, Polyak, Stephen J, Chung, Raymond T, Yarmush, Martin L, Nahmias, Yaakov
Format:	Article
Language:	eng
Subjects:	Anilides - pharmacology Anti-Ulcer Agents - pharmacology Apolipoprotein B-100 - metabolism Biological and medical sciences Brefeldin A - pharmacology Carrier Proteins - metabolism Cell Line, Tumor Citrus paradisi - chemistry Flavanones - pharmacology Gastroenterology and Hepatology Gastroenterology. Liver. Pancreas. Abdomen HCV Hepacivirus - drug effects Hepacivirus - growth & development Hepacivirus - metabolism Hepatocytes - metabolism Humans Lipid metabolism Lipoproteins, VLDL - biosynthesis Medical sciences Naringenin PPAR gamma - drug effects PPAR gamma - metabolism PPARα RNA, Viral - metabolism Viral Core Proteins - metabolism Virus Assembly - drug effects
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Background & Aims Hepatitis C virus (HCV) infection affects 3% of the world population and is the leading cause of chronic liver disease worldwide. Current standard of care is effective in only 50% of the patients, poorly tolerated, and associated with significant side effects and viral resistance. Recently, our group and others demonstrated that the HCV lifecycle is critically dependent on host lipid metabolism and that its production is metabolically modulated. Methods The JFH1/Huh7.5.1 full lifecycle model of HCV was used to study the antiviral effects of naringenin on viral replication, assembly, and production. Activation of PPARα was elucidated using GAL4-PPARα fusion reporters, PPRE reporters, qRT-PCR, and metabolic studies. Metabolic results were confirmed in primary human hepatocytes. Results We demonstrate that the grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. We show that naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000 U of interferon. During the washout period, HCV levels returned to normal, consistent with our proposed mechanism of action. Conclusions The data demonstrates that naringenin is a non-toxic assembly inhibitor of HCV and that other PPARα agonists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response.
ISSN:	0168-8278 1600-0641