Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis
Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis
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DOI：
10.1161/circulationaha.116.024503
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发表时间：
2017-04-04
期刊：
影响因子：
37.8
通讯作者：
Xia, Min
中科院分区：
文献类型：
--
作者：
Liu, Yan;Zhong, Yuan;Xia, Min
背景：视黄醇结合蛋白4 （RBP4）是一种脂肪因子，在葡萄糖代谢和胰岛素敏感性中起决定性作用。据报道，循环RBP4水平升高与心血管疾病风险增加有关，但RBP4在动脉粥样硬化性疾病中的确切作用及其作用机制尚不清楚。方法：对1683名华南地区参与者的血清RBP4水平进行评估，并对主要心血管不良事件的发生进行5年的随访。利用转染RBP4过表达/沉默腺病毒、J774A. 1巨噬细胞和RBP4转基因小鼠原代腹腔巨噬细胞的载脂蛋白e缺陷小鼠，研究了RBP4在泡沫细胞形成中的功能。结果：前瞻性队列研究显示，在调整传统危险因素后，基线血清RBP4水平是不良心血管事件发生率的独立预测因子。在人和载脂蛋白e缺陷小鼠的主动脉标本的动脉粥样硬化病变中，RBP4表达增加，并且RBP4定位于巨噬细胞泡沫细胞丰富的区域。在载脂蛋白e缺乏小鼠中，RBP4抑制减弱，而过表达加速动脉粥样硬化进展。外源性重组RBP4处理和RBP4基因的过表达均通过激活清除受体CD36介导的胆固醇摄取来促进巨噬细胞来源的泡沫细胞形成，RBP4以依赖于jun n -末端激酶和转录信号转导和激活因子1的方式上调CD36的表达。酪氨酸激酶c-Src被确定为jun n端激酶信号转换器的上游调节剂和转录1介导的cd36依赖性胆固醇摄取的激活剂，RBP4挑战被发现改变c-Src的膜分布并导致c-Src分裂到脂质筏膜亚域，在那里激酶被激活。最后，toll样受体4介导了RBP4在巨噬细胞中的诱导作用，而不是视黄醇或视黄酸6的刺激。结论：在传统模型中纳入RBP4水平可增强对动脉粥样硬化事件发生率的预测能力。RBP4通过诱导巨噬细胞衍生泡沫细胞形成促进动脉粥样硬化。
BACKGROUND: Retinol-binding protein 4 (RBP4) is an adipokine that plays decisive roles in glucose metabolism and insulin sensitivity. Elevated circulating RBP4 levels were reported to be associated with increased risk for cardiovascular disease, but the precise role of RBP4 in atherosclerotic diseases and its mechanisms of action remain elusive.METHODS: Serum RBP4 levels of 1683 participants from South China were evaluated and the occurrence of major adverse cardiovascular events was followed up for 5 years. Apolipoprotein E-deficient mice infected with RBP4-overexpressing/silencing adenovirus, J774A. 1 macrophages, and primary peritoneal macrophages from RBP4 transgenic mice were used for investigating the function of RBP4 in foam cell formation.RESULTS: Prospective cohort studies revealed that baseline serum RBP4 level was an independent predictor for incidence of adverse cardiovascular events after adjustment for traditional risk factors. Increased RBP4 expression was observed in atherosclerotic lesions of aortic specimens from both humans and apolipoprotein E-deficient mice, and RBP4 was localized to areas rich in macrophage foam cells. RBP4 inhibition attenuated whereas overexpression accelerated atherosclerosis progression in apolipoprotein E-deficient mice. Both treatment with exogenous recombinant RBP4 and overexpression of RBP4 gene promoted macrophage-derived foam cell formation through the activation of scavenger-receptor CD36-mediated cholesterol uptake, and RBP4 transcriptionally upregulated CD36 expression in a manner dependent on jun N-terminal kinase and signal transducer and activator of transcription 1. The tyrosine kinase c-Src was identified as the upstream regulator of jun N-terminal kinase-signal transducer and activator of transcription 1-mediated CD36-dependent cholesterol uptake, and RBP4 challenge was found to alter the membrane distribution of c-Src and cause c-Src to partition into lipid-raft membrane subdomains, where the kinase was activated. Lastly, Toll-like receptor 4, but not retinol or stimulated by retinoic acid 6, mediated the inductive effects of RBP4 in macrophages.CONCLUSIONS: Inclusion of RBP4 levels in traditional models enhances the predictive ability for the incidence of atherosclerotic events. RBP4 promotes atherogenesis by inducing macrophage-derived foam cell formation.