Inhibition of LXRα-dependent steatosis and oxidative injury by liquiritigenin, a licorice flavonoid, as mediated with Nrf2 activation

Antioxid Redox Signal. 2011 Mar 1;14(5):733-45. doi: 10.1089/ars.2010.3260. Epub 2010 Nov 1.

Abstract

Liver X receptor-α (LXRα) functions as a major regulator of lipid homeostasis through activation of sterol regulatory element binding protein-1c (SREBP-1c), which promotes hepatic steatosis and steatohepatitis. NF-E2-related factor 2 (Nrf2) is the crucial transcription factor that is necessary for the induction of antioxidant enzymes. This study investigated the potential of liquiritigenin (LQ), a hepatoprotective flavonoid in licorice, to inhibit LXRα-induced hepatic steatosis, and the underlying mechanism of the action. LQ treatment attenuated fat accumulation and lipogenic gene induction in the liver of mice fed a high fat diet. Also, LQ had the ability to inhibit oxidative liver injury, as shown by decreases in thiobarbituric acid reactive substances formation and nitrotyrosinylation. Moreover, LQ treatment antagonized LXRα agonist (T0901317)-mediated SREBP-1c activation, and transactivation of the lipogenic target genes. LQ was found to activate Nrf2, and the ability of LQ to inhibit LXRα-mediated SREBP-1c activation was reversed by Nrf2 deficiency, which supports the inhibitory role of Nrf2 in LXRα-dependent lipogenesis. Consistently, treatment with other Nrf2 activators or forced expression of Nrf2 also inhibited LXRα-mediated SREBP-1c activation. Our results demonstrate that LQ has an efficacy to activate Nrf2, which contributes to inhibiting the activity of LXRα that leads to SREBP-1c induction and hepatic steatosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cell Line
  • Dietary Fats / metabolism
  • Fatty Liver / pathology*
  • Flavanones / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glycyrrhiza / chemistry
  • Hep G2 Cells
  • Humans
  • Hydrocarbons, Fluorinated / antagonists & inhibitors
  • Hydrocarbons, Fluorinated / metabolism
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Orphan Nuclear Receptors / antagonists & inhibitors*
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Oxidative Stress / drug effects*
  • Rats
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sulfonamides / antagonists & inhibitors
  • Sulfonamides / metabolism

Substances

  • Antioxidants
  • Dietary Fats
  • Flavanones
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NF-E2-Related Factor 2
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • TO-901317
  • liquiritigenin