title: Inhibition of LXRα-dependent steatosis and oxidative injury by liquiritigenin, a licorice flavonoid, as mediated with Nrf2 activation.
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.
authors.affiliation: Innovative Drug Research Center for Metabolic and Inflammatory Diseases, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Kim
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Yoon Mee
authors.initials: YM
authors.lastname: Yang
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kay
authors.forename: Won Dong
authors.initials: WD
authors.lastname: Kim
authors.forename: Jee Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004041:Dietary Fats / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology*; D044950:Flavanones / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006035:Glycyrrhiza / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000037:antagonists & inhibitors / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000037:antagonists & inhibitors / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000975:Antioxidants; D004041:Dietary Fats; D044950:Flavanones; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D051267:NF-E2-Related Factor 2; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C083152:liquiritigenin