Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein
Activation of Peroxisome Proliferator-Activated Receptor δ Inhibits Human Macrophage Foam Cell Formation and the Inflammatory Response Induced by Very Low-Density Lipoprotein
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DOI：
10.1161/atvbaha.112.255208
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发表时间：
2012-12-01
影响因子：
8.7
通讯作者：
Huff, Murray W.
中科院分区：
文献类型：
--
作者：
Bojic, Lazar A.;Sawyez, Cynthia G.;Huff, Murray W.
目的：高甘油三酯血症是心血管疾病的重要危险因素。血浆极低密度脂蛋白(VLDL)升高使胰岛素抵抗患者面临动脉粥样硬化的风险。极低密度脂蛋白很容易诱导巨噬细胞脂质堆积和炎症反应，对此，有针对性的治疗策略仍然难以捉摸。我们检测了极低密度脂蛋白诱导巨噬细胞泡沫细胞和炎症反应的能力，并试图确定所涉及的细胞信号级联反应。我们进一步研究了过氧化体增殖物激活受体(PPAR)增量激活抑制VLDL刺激的脂质堆积和细胞因子表达的可能性。方法和结果-暴露于VLDL的THP-1巨噬细胞表现出显著的甘油三酯积聚，这种积聚可被PPAR增量激活所减弱。PPAR Delta激动剂刺激转录程序，导致抑制脂蛋白脂肪酶活性，激活脂肪酸摄取，并增强β-氧化。极低密度脂蛋白处理的巨噬细胞表达活化蛋白1相关细胞因子白介素1β、巨噬细胞炎性蛋白1α和细胞间黏附分子1。极低密度脂蛋白处理显著增加细胞外信号相关激酶1和2以及p38的磷酸化。极低密度脂蛋白降低AKT磷酸化及其下游效应叉头盒蛋白O1，伴随着核叉头盒蛋白O1的增加。经PPAR Delta激动剂处理的细胞完全抵抗VLDL诱导的炎症细胞因子的表达，这是通过丝裂原活化蛋白激酶(MAPK)和AKT/叉头盒蛋白O1信号的正常化来介导的。结论：PPAR Delta联合介导的脂质堆积和炎性细胞因子表达的减少为治疗动脉粥样硬化提供了一种新的巨噬细胞靶向治疗选择。(动脉血栓血管生物)2012；32：2919-2928。)
Objective-Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients a risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) delta activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression.Methods and Results-THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPAR delta activation. PPAR delta agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced beta-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1 beta, macrophage inflammatory protein 1 alpha, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPAR delta agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)(crk) and AKT/forkhead box protein O1 signaling.Conclusion-The combined PPAR delta-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis. (Arterioscler Thromb Vasc Biol. 2012;32:2919-2928.)