Inhibition of LXR alpha-Dependent Steatosis and Oxidative Injury by Liquiritigenin, a Licorice Flavonoid, as Mediated with Nrf2 Activation (Retracted article. See vol. 16, pg. 292, 2012)

Abstract

Liver X receptor-alpha (LXR alpha) 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 LXR alpha-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 LXRa agonist (T0901317)-mediatedSREBP-1c activation, and transactivation of the lipogenic target genes. LQ was found to activate Nrf2, and the ability of LQ to inhibit LXR alpha-mediated SREBP-1c activation was reversed by Nrf2 deficiency, which supports the inhibitory role of Nrf2 in LXR alpha-dependent lipogenesis. Consistently, treatment with other Nrf2 activators or forced expression of Nrf2 also inhibited LXR alpha-mediated SREBP-1c activation. Our results demonstrate that LQ has an efficacy to activate Nrf2, which contributes to inhibiting the activity of LXRa that leads to SREBP-1c induction and hepatic steatosis. Antioxid. Redox Signal. 14, 733-745.