Modulation of PI3K-LXRα-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin

Lab Invest. 2014 Mar;94(3):262-74. doi: 10.1038/labinvest.2013.156. Epub 2014 Feb 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Antiviral Agents / pharmacology*
  • Apigenin / pharmacology
  • Cell Line
  • Chromones / pharmacology
  • Down-Regulation / drug effects
  • Fatty Acids, Nonesterified / metabolism
  • Hepacivirus / drug effects*
  • Hepacivirus / physiology*
  • Humans
  • Kaempferols / pharmacology
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver X Receptors
  • Morpholines / pharmacology
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quercetin / analogs & derivatives
  • Quercetin / pharmacology*
  • Reactive Nitrogen Species / metabolism
  • Signal Transduction / drug effects
  • Triglycerides / metabolism
  • Virus Replication / drug effects*

Substances

  • Antioxidants
  • Antiviral Agents
  • Chromones
  • Fatty Acids, Nonesterified
  • Kaempferols
  • Liver X Receptors
  • Morpholines
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • Phosphoinositide-3 Kinase Inhibitors
  • Reactive Nitrogen Species
  • Triglycerides
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • kaempferol
  • Apigenin
  • Quercetin
  • taxifolin
  • Proto-Oncogene Proteins c-akt