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

Center for Engineering in Medicine, Shriners Burns Hospital, Boston, MA, USA.
Hepatology (Impact Factor: 11.06). 05/2008; 47(5):1437-45. DOI: 10.1002/hep.22197
Source: PubMed


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. CONCLUSION: These results suggest a novel therapeutic approach for the treatment of HCV infection.

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Available from: Yaakov Nahmias, Apr 10, 2015
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    • "HCV core protein and ApoB100 in culture supernatants were measured using Ortho Ò HCV core antigen ELISA (Wako Chemicals) and Alerchek's Human ApoB100 ELISA, respectively, as previously described [15]. "
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    • "Few of the plant derived dietary components have been explored for their abilities to interfere with all possible stages of HCV life cycle via different mechanisms and proved valuable to HCV therapy. Recently, naringenin (grapes) has been shown to inhibit apolipoprotein B-dependent secretion of HCV particles5. Proanthocyanidin (blueberry) suppresses HCV replication, possibly by interacting with hnRNP A2/B6. "
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    ABSTRACT: Hepatitis C virus (HCV) is the causative agent of end-stage liver disease. Recent advances in the last decade in anti HCV treatment strategies have dramatically increased the viral clearance rate. However, several limitations are still associated, which warrant a great need of novel, safe and selective drugs against HCV infection. Towards this objective, we explored highly potent and selective small molecule inhibitors, the ellagitannins, from the crude extract of Pomegranate (Punica granatum) fruit peel. The pure compounds, punicalagin, punicalin, and ellagic acid isolated from the extract specifically blocked the HCV NS3/4A protease activity in vitro. Structural analysis using computational approach also showed that ligand molecules interact with the catalytic and substrate binding residues of NS3/4A protease, leading to inhibition of the enzyme activity. Further, punicalagin and punicalin significantly reduced the HCV replication in cell culture system. More importantly, these compounds are well tolerated ex vivo and'no observed adverse effect level' (NOAEL) was established upto an acute dose of 5000 mg/kg in BALB/c mice. Additionally, pharmacokinetics study showed that the compounds are bioavailable. Taken together, our study provides a proof-of-concept approach for the potential use of antiviral and non-toxic principle ellagitannins from pomegranate in prevention and control of HCV induced complications.
    Scientific Reports 06/2014; 4:5411. DOI:10.1038/srep05411 · 5.58 Impact Factor
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    • "Recent studies suggest intracellular APOE facilitates lipid recruitment at different stages of very low-density lipoprotein (VLDL) assembly and trafficking through the endoplasmic reticulum-Golgi secretory compartments [41]. To date, mounting evidence indicated that HCV exploits the hosts’ pathway of producing VLDLs to assemble and secrete virions [42]–[45]. One possibility is that GP73 enhances HCV secretion through increasing the assembly and secretion of VLDL by upregulating intracellular APOE. "
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    ABSTRACT: Hepatitis C virus (HCV) is a major cause of chronic liver disease. However, little is known about the details of its assembly and secretion. Golgi-related proteins have been recently proven to have a key function in HCV secretion. Golgi protein 73 (GP73), a resident Golgi membrane protein, is a potential serum biomarker for the diagnosis of liver diseases and hepatocellular carcinoma. Previous studies have demonstrated the upregulation of GP73 in the liver samples and sera of HCV-infected patients. However, the function and regulatory mechanism of GP73 in HCV infection at the cellular level remain unknown. In this study, we examined the expression level of GP73 in HCV infected cells and its effect on HCV life cycle in cell culture systems. Both the protein expression and mRNA levels of GP73 significantly increased in HCV subgenomic replicon-harboring cells and HCV-infected cells, which imply that GP73 was upregulated by HCV infection. HCV production was significantly enhanced when GP73 was overexpressed, but dramatically inhibited when GP73 was silenced. However, the overexpression and knockdown of GP73 showed no evident effect on the entry, protein translation, RNA replication, and assembly of HCV, which indicates that GP73 enhanced the secretion process. Moreover, the coiled-coil domain of GP73 was required to increase HCV secretion. GP73 increased and interacted with apolipoprotein E, an identified host factor that assists in HCV secretion. These results demonstrate the critical function of GP73 in HCV secretion and provide new insights into the therapeutic design of antiviral strategies.
    PLoS ONE 03/2014; 9(3):e90553. DOI:10.1371/journal.pone.0090553 · 3.23 Impact Factor
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