A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity
A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity
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DOI：
10.15252/embj.201489527
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发表时间：
2015-01-14
期刊：
影响因子：
11.4
通讯作者：
Kemper, Jongsook Kim
中科院分区：
文献类型：
--
作者：
Kim, Dong-Hyun;Xiao, Zhen;Kemper, Jongsook Kim
转录调节因子的乙酰化通常受营养状态的动态调节，但在营养过度肥胖的情况下经常持续升高。作为一个模型，我们研究了核受体FXR乙酰化异常升高的功能后果。蛋白质组学研究确定K217是饮食诱导的肥胖小鼠中的FXR乙酰化位点。利用乙酰化模拟和乙酰化缺陷的K217突变体和基因表达谱进行的体内研究表明，FXR乙酰化增加了促炎基因的表达，巨噬细胞的浸润，以及肝脏细胞因子和甘油三酯的水平，削弱了胰岛素信号，并增加了葡萄糖耐量。机制上，FXR的乙酰化阻止了其与相扑连接酶PIASy的相互作用，并抑制了K277处的SUMO2修饰，导致炎症基因的激活。激动剂激活的FXR的SUMO化增加了其与NF-B的相互作用，但阻断了与RXR的相互作用，从而使SUMO2修饰的FXR选择性地募集到并反式抑制了炎症基因，而不影响FXR/RXR靶基因。肥胖时FXR的乙酰/相扑开关失调可能是其他转录调节因子抗炎反应减弱的一般机制，并为肥胖相关代谢紊乱提供潜在的治疗和诊断靶点。
Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-B but blocked that with RXR, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXR target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.