論文 - 詳細
| RRC ID | 11867 |
|---|---|
| 著者 | Kay HY, Kim WD, Hwang SJ, Choi HS, Gilroy RK, Wan YJ, Kim SG. |
| タイトル | Nrf2 inhibits LXRα-dependent hepatic lipogenesis by competing with FXR for acetylase binding. |
| ジャーナル | Antioxid Redox Signal |
| Abstract |
AIMS: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. INNOVATION: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. CONCLUSION: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. |
| 巻・号 | 15(8) |
| ページ | 2135-46 |
| 公開日 | 2011-10-15 |
| DOI | 10.1089/ars.2010.3834 |
| PMID | 21504366 |
| PMC | PMC6468953 |
| MeSH | Acetylesterase / genetics Acetylesterase / metabolism* Animals Blotting, Western Chromatin Immunoprecipitation Fatty Liver / chemically induced Fatty Liver / metabolism Hep G2 Cells Hepatocytes / drug effects Hepatocytes / metabolism Humans Hydrocarbons, Fluorinated / pharmacology Immunoprecipitation Isothiocyanates Lipogenesis / drug effects Lipogenesis / genetics Liver / drug effects* Liver / metabolism* Liver X Receptors Male Mice Mice, Inbred C57BL Mice, Knockout NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism* Orphan Nuclear Receptors / agonists Orphan Nuclear Receptors / metabolism* Protein Binding / drug effects Real-Time Polymerase Chain Reaction Receptors, Cytoplasmic and Nuclear / genetics Receptors, Cytoplasmic and Nuclear / metabolism* Sterol Regulatory Element Binding Protein 1 / genetics Sterol Regulatory Element Binding Protein 1 / metabolism Sulfonamides / pharmacology Sulfoxides Thiocyanates / pharmacology |
| IF | 7.04 |
| 引用数 | 62 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM BIOCHEMISTRY & MOLECULAR BIOLOGY |
| リソース情報 | |
| 実験動物マウス | RBRC01390 |