Vascular Biology, Robarts Research Institute, Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada.
Arterioscler Thromb Vasc Biol. 2012 Dec;32(12):2919-28. doi: 10.1161/ATVBAHA.112.255208. Epub 2012 Sep 27.
Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at 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) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression.
THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced β-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1β, macrophage inflammatory protein 1α, 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 PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)(erk) and AKT/forkhead box protein O1 signaling.
The combined PPARδ-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.
高甘油三酯血症是心血管疾病的一个重要危险因素。升高的血浆极低密度脂蛋白（VLDL）使胰岛素抵抗患者易患动脉粥样硬化。VLDL 容易诱导巨噬细胞脂质积累和炎症反应，针对这些反应的靶向治疗策略仍然难以捉摸。我们研究了 VLDL 诱导巨噬细胞泡沫细胞和炎症反应的能力，并试图确定涉及的细胞信号级联。我们进一步研究了过氧化物酶体增殖物激活受体（PPAR）δ激活的潜力，以减轻 VLDL 刺激的脂质积累和细胞因子表达。
暴露于 VLDL 的 THP-1 巨噬细胞显示出明显的甘油三酯积累，这可以通过 PPARδ 激活来减弱。PPARδ 激动剂刺激转录程序，导致脂蛋白脂肪酶活性抑制、脂肪酸摄取激活和β氧化增强。VLDL 处理的巨噬细胞显著增加了与激活蛋白 1 相关的细胞因子白细胞介素 1β、巨噬细胞炎症蛋白 1α 和细胞间黏附分子 1 的表达。VLDL 处理显著增加了细胞外信号相关激酶 1 和 2 以及 p38 的磷酸化。VLDL 降低了 AKT 的磷酸化及其下游效应物叉头框蛋白 O1，同时增加了核叉头框蛋白 O1。用 PPARδ 激动剂处理的细胞完全抵抗 VLDL 诱导的炎症细胞因子表达，这是通过 MAPK（erk）和 AKT/forkhead box protein O1 信号的正常化介导的。
PPARδ 介导的脂质积累和炎症细胞因子表达的减少表明，在治疗动脉粥样硬化方面，针对巨噬细胞的新型靶向治疗选择是可行的。
