title: Nrf2 inhibits LXRα-dependent hepatic lipogenesis by competing with FXR for acetylase binding.
abstract: OBJECTIVE
  The nuclear receptor liver X receptor-α (LXRα) stimulates lipogenesis, leading to steatosis. Nuclear factor erythroid-2-related factor-2 (Nrf2) contributes to cellular defense mechanism by upregulating antioxidant genes, and may protect the liver from injury inflicted by fat accumulation. However, whether Nrf2 affects LXRα activity is unknown. This study investigated the inhibitory role of Nrf2 in hepatic LXRα activity and the molecular basis.
  
  
  RESULTS
  A deficiency of Nrf2 enhanced the ability of LXRα agonist to promote hepatic steatosis, as mediated by lipogenic gene induction. In hepatocytes, Nrf2 overexpression repressed gene transactivation by LXR-binding site activation. Consistently, treatment of mice with sulforaphane (an Nrf2 activator) suppressed T0901317-induced lipogenesis, as confirmed by the experiments using hepatocytes. Nrf2 activation promoted deacetylation of farnesoid X receptor (FXR) by competing for p300, leading to FXR-dependent induction of small heterodimer partner (SHP), which was responsible for the repression of LXRα-dependent gene transcription. In human steatotic samples, the transcript levels of LXRα and SREBP-1 inversely correlated with those of Nrf2, FXR, and SHP.
  
  
  METHODS
  Our findings offer the mechanism to explain how decrease in Nrf2 activity in hepatic steatosis could contribute to the progression of NAFLD, providing the use of Nrf2 as a molecular biomarker to diagnose NAFLD. As certain antioxidants have the abilities to activate Nrf2, clinicians might utilize the activators of Nrf2 as a new therapeutic approach to prevent and/or treat NAFLD.
  
  
  CONCLUSIONS
  Nrf2 activation inhibits LXRα activity and LXRα-dependent liver steatosis by competing with FXR for p300, causing FXR activation and FXR-mediated SHP induction. Our findings provide important information on a strategy to prevent and/or treat steatosis.
authors.affiliation: Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kay
authors.forename: Won Dong
authors.initials: WD
authors.lastname: Kim
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gilroy
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000115:Acetylesterase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D047468:Immunoprecipitation; D017879:Isothiocyanates; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000115:Acetylesterase; D006845:Hydrocarbons, Fluorinated; D017879:Isothiocyanates; D000071518:Liver X Receptors; D051267:NF-E2-Related Factor 2; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D013454:Sulfoxides; D013861:Thiocyanates; D000099150:Receptor, Farnesoid X-Activated; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C016766:sulforaphane