Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin

Yaakov Nahmias*, Jonathan Goldwasser, Monica Casali, Daan Van Poll, Takaji Wakita, Raymond T. Chung, Martin L. Yarmush

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

232 Scopus citations

Abstract

Hepatitis C virus (HCV) infects over 3% of the world population and is the leading cause of chronic liver disease worldwide. HCV has long been known to associate with circulating lipoproteins, and its interactions with the cholesterol and lipid pathways have been recently described. In this work, we demonstrate that HCV is actively secreted by infected cells through a Golgi-dependent mechanism while bound to very low density lipoprotein (vLDL). Silencing apolipoprotein B (ApoB) messenger RNA in infected cells causes a 70% reduction in the secretion of both ApoB-100 and HCV. More importantly, we demonstrate that the grapefruit flavonoid naringenin, previously shown to inhibit vLDL secretion both in vivo and in vitro, inhibits the microsomal triglyceride transfer protein activity as well as the transcription of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and acyl-coenzyme Archolesterol acyltransferase 2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80%. Moreover, we find that naringenin is effective at concen-trations that are an order of magnitude below the toxic threshold in primary human hepatocytes and in mice. Conclusion: These results suggest a novel therapeutic approach for the treatment of HCV infection.

Original languageAmerican English
Pages (from-to)1437-1445
Number of pages9
JournalHepatology
Volume47
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

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