Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin.
There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 μM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)α. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)α-induced lipid accumulation in LXRα-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRα-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRα upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRα-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRα-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication.
Institute of Biomedicine (IBIOMED), University of León, León, Spain.
Sandra
S
Pisonero-Vaquero
1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
María V
MV
García-Mediavilla
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Department of Gastroenterology, Complejo Asistencial Universitario de León, León, Spain.
Francisco
F
Jorquera
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Molecular Biology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
Pedro L
PL
Majano
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain.
Marta
M
Benet
1] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain [2] Experimental Hepatology Unit, IIS Hospital La Fe, Valencia, Spain [3] Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain.
Ramiro
R
Jover
1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
Javier
J
González-Gallego
1] Institute of Biomedicine (IBIOMED), University of León, León, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
Sonia
S
Sánchez-Campos
D000975:Antioxidants / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D044949:Kaempferols / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D000071518:Liver X Receptors; D009025:Morpholines / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D000975:Antioxidants; D000998:Antiviral Agents; D047310:Apigenin; D002867:Chromones; D005230:Fatty Acids, Nonesterified; D044949:Kaempferols; D000071518:Liver X Receptors; D009025:Morpholines; D057093:Orphan Nuclear Receptors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011794:Quercetin; D026361:Reactive Nitrogen Species; D014280:Triglycerides; C000605213:NR1H3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C006552:kaempferol; C003377:taxifolin