Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis
Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis
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DOI：
10.1016/j.jacc.2018.12.055
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发表时间：
2019-03-19
影响因子：
24
通讯作者：
Erbay, Ebru
中科院分区：
文献类型：
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作者：
Onat, Umut I.;Yildirim, Asli D.;Erbay, Ebru
背景：真核细胞可以通过在真核细胞起始因子2α(EIF2a)的丝氨酸-51磷酸化处聚合，激活整合应激反应(ISR)来响应不同的刺激。这是翻译调控的关键一步，必须受到严格调控；然而，在小鼠和人类动脉粥样硬化中观察到持续的eIF2a磷酸化。目的：已经发现了调节神经退行性疾病的有效的ISR抑制剂。在这里，作者评估了在慢性代谢性和炎症性疾病动脉粥样硬化中拦截ISR的潜在好处。方法利用3种不同的小分子和ATP类似敏感蛋白等位基因技术在多个分子节点截获ISR，研究ISR在脂质诱导的炎性小体激活和动脉粥样硬化形成中的作用。结果脂质激活的eIF2a信号诱导线粒体蛋白水解酶Lon Protease1(LONP1)降解磷酸酶和张力蛋白诱导的蛋白激酶1，阻断Parkin介导的吞噬作用，导致巨噬细胞线粒体氧化应激、炎症体激活和IL-1b分泌增加。此外，ISR抑制剂可抑制高脂血症引起的炎性小体激活和炎症，减轻动脉粥样硬化。结论这些结果表明内质网通过激活eIF2aLONP1信号来控制线粒体的清除，从而导致放大的氧化应激反应，从而触发强烈的炎性小体激活和饮食脂肪分泌IL-1b。这些发现强调了复杂的信息交换和两个细胞器对脂质的反应的协调对于新陈代谢健康是重要的。调节ISR以减轻细胞器应激可以防止饮食脂肪激活炎症体，这可能是减少脂质诱导的炎症和动脉粥样硬化的一种策略。(J Am Coll心脏ol 2019；73：1149-69)(C)2019年作者。由爱思唯尔公司代表美国心脏病学会基金会出版。这是一篇CC BY-NC-ND许可证(http://creativecommons.)下的开放获取文章Org/许可证/by-nc-nd/4.0/)。
BACKGROUND Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2a) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2a phosphorylation is observed in mouse and human atheroma. OBJECTIVES Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis. METHODS The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes. RESULTS The results show lipid-activated eIF2a signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1b secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis. CONCLUSIONS These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2aLONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1b secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis. (J Am Coll Cardiol 2019; 73: 1149-69) (c) 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).