Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity.
Farnesoid X receptor-induced lysine-specific histone demethylase reduces hepatic bile acid levels and protects the liver against bile acid toxicity.
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Farnesoid X受体诱导的赖氨酸特异性组蛋白脱甲基酶降低肝胆酸水平，并保护肝脏免受胆汁酸毒性。
DOI：
10.1002/hep.27677
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发表时间：
2015-07
期刊：
影响因子：
13.5
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
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作者：
Kim, Young-Chae;Fang, Sungsoon;Byun, Sangwon;Seok, Sunmi;Kemper, Byron;Kemper, Jongsook Kim
胆汁酸 (BA) 作为内分泌信号分子，激活多个核和膜受体信号通路以控制进食状态代谢。由于 BA 具有类似清洁剂的特性，高浓度时会导致肝脏损伤，因此必须严格调节肝脏 BA 水平。 BA 稳态主要在转录水平上受到核受体的调节，特别是初级胆汁酸受体、法尼醇 X 受体 (FXR) 和小异二聚体伴侣 (SHP)，后者通过招募抑制性组蛋白修饰酶来抑制 BA 合成。尽管组蛋白修饰剂已被证明可以调节 BA 反应基因，但它们的体内功能仍不清楚。在这里，我们表明，赖氨酸特异性组蛋白去甲基化酶 1 (LSD1) 直接由 BA 激活的 FXR 诱导，被招募到 BA 合成基因 Cyp7a1 和 Cyp8b1 以及 BA 摄取转运蛋白基因 Ntcp，并去除基因激活标记，三甲基化组蛋白 H3 赖氨酸-4，从而导致基因抑制。 LSD1 的募集依赖于 SHP，并且 LSD1 介导的 H3K4-me3 去甲基化是额外的抑制性组蛋白修饰、H3K9/K14 脱乙酰化和 H3K9 甲基化所必需的。 BA 超载，饲喂 0.5% 胆酸饲料 6 天，导致参与 BA 合成、运输和解毒/结合的肝脏基因表达改变的适应性反应。相反，腺病毒介导的肝脏 LSD1 下调减弱了这些反应，导致肝脏和血清 BA 水平、血清 AST/ALT 水平和肝脏炎症大幅增加。这项研究将 LSD1 确定为一种新型组蛋白修饰酶，参与由 FXR 和 SHP 介导的精心策划的调节，可降低肝脏 BA 水平并保护肝脏免受 BA 毒性。
Bile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. BA homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary bile acid receptor, farnesoid X receptor (FXR), and small heterodimer partner (SHP) that inhibits BA synthesis by recruiting repressive histone-modifying enzymes. Although histone modifiers have been shown to regulate BA-responsive genes, their in vivo functions remain unclear. Here we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated FXR, is recruited to BA synthetic genes, Cyp7a1 and Cyp8b1, and the BA uptake transporter gene, Ntcp, and removes a gene-activation mark, tri-methylated histone H3 lysine-4, leading to gene repression. LSD1 recruitment was dependent on SHP, and LSD1-mediated demethylation of H3K4-me3 was required for additional repressive histone modifications, H3K9/K14 deacetylation and H3K9 methylation. BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenoviral-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum AST/ALT levels, and hepatic inflammation. This study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the FXR and SHP that reduces hepatic BA levels and protects the liver against BA toxicity.
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影响因子：
16
作者：
Mulligan P;Yang F;Di Stefano L;Ji JY;Ouyang J;Nishikawa JL;Toiber D;Kulkarni M;Wang Q;Najafi-Shoushtari SH;Mostoslavsky R;Gygi SP;Gill G;Dyson NJ;Näär AM
通讯作者：
Näär AM
影响因子：
25.7
作者：
Kosters, Astrid;Felix, Julio C.;Karpen, Saul J.
通讯作者：
Karpen, Saul J.
影响因子：
29.4
作者：
Modica, Salvatore;Petruzzelli, Michele;Moschetta, Antonio
通讯作者：
Moschetta, Antonio
影响因子：
13.5
作者：
Mitro, Nico;Godio, Cristina;Crestani, Maurizio
通讯作者：
Crestani, Maurizio
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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