Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin.
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 A:cholesterol acyltransferase 2 in infected cells. Stimulation with naringenin reduces HCV secretion in infected cells by 80%. Moreover, we find that naringenin is effective at concentrations that are an order of magnitude below the toxic threshold in primary human hepatocytes and in mice.


CONCLUSIONS
These results suggest a novel therapeutic approach for the treatment of HCV infection.
Nahmias
Yaakov
Y
Center for Engineering in Medicine, Shriners Burns Hospital, Boston, MA, USA. ynahmias@partners.org
Goldwasser
Jonathan
J
Casali
Monica
M
van Poll
Daan
D
Wakita
Takaji
T
Chung
Raymond T
RT
Yarmush
Martin L
ML
D001055:Apolipoproteins B / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D032083:Citrus paradisi; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D044950:Flavanones / Q000494:pharmacology*; D020868:Gene Silencing; D016174:Hepacivirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014758:Viral Core Proteins / Q000032:analysis
D001055:Apolipoproteins B; D017931:DNA Primers; D044950:Flavanones; D012333:RNA, Messenger; D014758:Viral Core Proteins; C005273:naringenin