目的:代谢改变是巨噬细胞(MΦ)表型的重要调节因子,这有助于炎性疾病,如动脉粥样硬化。广义上,促炎,经典激活的MΦ(CAM)是糖酵解的,而交替激活的MΦ(AAM)氧化脂肪酸,尽管存在重叠。我们先前证明,在饮食诱导的肥胖模型中,MΦ脂肪酸转运蛋白1(FATP1,Slc27a1)对于维持体内氧化和抗炎AAM表型是必需的。这项研究的目的是研究通过FATP1消融的MΦ代谢重编程如何影响动脉粥样硬化形成过程。我们假设FATP1限制了动脉粥样硬化形成过程中MΦ介导的炎症。因此,缺乏MΦFatp1的小鼠在缺乏低密度脂蛋白(LDL)受体(Ldlr-/-)的小鼠模型中显示动脉粥样硬化病变的形成增加。
方法:我们将从Fatp1+/+或Fatp1-/-小鼠收集的骨髓移植到Ldlr-/-小鼠中,并给嵌合小鼠喂食Western饮食12周。体重,血糖,和测量血浆脂质。对主动脉窦和主动脉病变进行定量。动脉粥样硬化斑块组成,氧化应激,和炎症进行组织学分析。
结果:与Fatp1+/+Ldlr-/-小鼠相比,Fatp1-/-Ldlr-/-小鼠表现出明显更大的病变面积,并且在动脉粥样硬化斑块中氧化应激和炎症反应升高。巨噬细胞和平滑肌细胞含量因Fatp1基因型而异。LDL没有明显的全身性改变,高密度脂蛋白(HDL),总胆固醇,或者三酰甘油酯,这表明该效应以Fatp1依赖性方式存在于血管微环境的细胞中。
结论:MΦFatp1限制动脉粥样硬化形成,可能是代谢重编程MΦ的可行靶标。
OBJECTIVE: Altered metabolism is an important regulator of macrophage (MΦ) phenotype, which contributes to inflammatory diseases such as atherosclerosis. Broadly, pro-inflammatory, classically-activated MΦs (CAM) are glycolytic while alternatively-activated MΦs (AAM) oxidize fatty acids, although overlap exists. We previously demonstrated that MΦ fatty acid transport protein 1 (FATP1, Slc27a1) was necessary to maintain the oxidative and anti-inflammatory AAM phenotype in vivo in a model of diet-induced obesity. The aim of this study was to examine how MΦ metabolic reprogramming through FATP1 ablation affects the process of atherogenesis. We hypothesized that FATP1 limits MΦ-mediated inflammation during atherogenesis. Thus, mice lacking MΦ Fatp1 would display elevated formation of atherosclerotic lesions in a mouse model lacking the low-density lipoprotein (LDL) receptor (Ldlr-/-).
METHODS: We transplanted bone marrow collected from Fatp1+/+ or Fatp1-/- mice into Ldlr-/- mice and fed chimeric mice a Western diet for 12 weeks. Body weight, blood glucose, and plasma lipids were measured. Aortic sinus and aorta lesions were quantified. Atherosclerotic plaque composition, oxidative stress, and inflammation were analyzed histologically.
RESULTS: Compared to Fatp1+/+Ldlr-/- mice, Fatp1-/-Ldlr-/- mice exhibited significantly larger lesion area and elevated oxidative stress and inflammation in the atherosclerotic plaque. Macrophage and smooth muscle cell content did not differ by Fatp1 genotype. There were no significant systemic alterations in LDL, high-density lipoprotein (HDL), total cholesterol, or triacylglyceride, suggesting that the effect was local to the cells of the vessel microenvironment in a Fatp1-dependent manner.
CONCLUSIONS: MΦ Fatp1 limits atherogenesis and may be a viable target to metabolically reprogram MΦs.