Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.
Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells.
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Foxo3a 依赖性 Bim 转录通过促进 Kupffer 细胞中的自噬流来抑制 NLRP3 炎症小体的激活，从而保护小鼠免受高脂肪饮食的影响
DOI：
10.18632/oncotarget.15946
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发表时间：
2017-05-23
期刊：
影响因子：
--
通讯作者：
Gong J
中科院分区：
文献类型：
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作者：
Liu Y;Zhang W;Wu X;Gong J
Foxo3a在HFD条件下KC中自噬通量和NLRP 3炎性体活化的调节中的作用尚不清楚。结果Foxo3a的上调可恢复PA和LPS刺激的KC的自噬流，抑制NLRP 3炎性体的活化。相反，下调Foxo3a增加了自噬通量的阻断，并促进了NLRP 3炎性小体的激活。此外，在foxo3a靶基因中，在PA和LPS刺激下，KC中Bim的mRNA水平随着foxo3a的改变而显著改变。Bim的过表达恢复了自噬流入并减弱了NLRP3炎性体通路的激活。此外，自噬形成恢复，并且在从用伊图里蛋白A处理并用HFD喂养的小鼠分离的KC中抑制NLRP 3炎性体的活化。材料与方法在用PA和LPS刺激前改变KC中Foxo3a的表达后，评价KC中的自噬通量和NLRP 3炎性体的活化水平。此外，在用PA和LPS刺激KC后，在用Foxo 3a激动剂（Iturin A）或抑制剂（SC 97）预处理的KC中测量Foxo 3a的各种靶基因，以寻找Foxo 3a的靶点。在用伊都灵A处理小鼠并用HFD喂养16周后，测量分离的KC中NLRP 3炎性体的活化水平以及自噬通量。结论Foxo3a通过促进Bim的转录，恢复自噬流，减弱NLRP 3炎性小体的激活，提示Foxo3a可能是NAFLD等肥胖相关疾病的治疗靶点。
Background The role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown. Results Up-regulation of Foxo3a restored autophagy flux and dampened the activation of the NLRP3 inflammasome in KCs stimulated with PA and LPS. In contrast, down-regulation of Foxo3a increased blockage of autophagy flux and promoted NLRP3 inflammasome activation. Additionally, mRNA levels of Bim were significantly changed with the alteration of Foxo3a in KCs under PA and LPS stimulation among foxo3a targeted genes. Overexpression of Bim restored autophagy influx and attenuated NLRP3 inflammasome pathway activation. In addition, autophagy formation was restored, and activation of NLRP3 inflammasome was inhibited in KCs isolated from mice treated with Iturin A and fed with a HFD. Materials and methods Autophagy flux in KCs and activation levels of NLRP3 inflammasome were evaluated after altering the expression of Foxo3a in KCs before stimulation with PA and LPS. Additionally, various target genes of Foxo3a were measured in KCs pretreated with an agonist (Iturin A) or inhibitor (SC97) of Foxo3a after KCs stimulation with PA and LPS in order to hunt for targets of Foxo3a. Activation levels of NLRP3 inflammasome in isolated KCs, as well as autophagy flux, were measured after mice were treated with Iturin A and fed with a HFD for 16 weeks. Conclusions Foxo3a restores autophagy flux and attenuates the activation of the NLRP3 inflammasome by promoting the transcription of Bim, suggesting a potential therapeutic target in NAFLD and other obesity-related diseases.