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首页> 外文期刊>Cell death & disease. >PPARα and PPARγ activation attenuates total free fatty acid and triglyceride accumulation in macrophages via the inhibition of Fatp1 expression
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PPARα and PPARγ activation attenuates total free fatty acid and triglyceride accumulation in macrophages via the inhibition of Fatp1 expression

机译：PPARα和PPARγ活化通过抑制FATP1表达抑制巨噬细胞中的总无脂肪酸和甘油三酯积累

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Lipid accumulation in macrophages interacts with microenvironment signals and accelerates diabetic atherosclerosis. However, the molecular mechanisms by which macrophage metabolism interacts with microenvironment signals during lipid accumulation are not clearly understood. Accordingly, an untargeted metabolomics approach was employed to characterize the metabolic reprogramming, and to identify potential regulatory targets related to lipid accumulation in macrophages treated with oleate, an important nutrient. The metabolomics approach revealed that multiple metabolic pathways were significantly disturbed in oleate-treated macrophages. We discovered that amino acids, nucleosides, lactate, monoacylglycerols, total free fatty acids (FFAs), and triglycerides (TGs) accumulated in oleate-treated macrophages, but these effects were effectively attenuated or even abolished by resveratrol. Notably, 1-monooleoylglycerol and 2-monooleoylglycerol showed the largest fold changes in the levels among the differential metabolites. Subsequently, we found that oleate triggered total FFA and TG accumulation in macrophages by accelerating FFA influx through the activation of Fatp1 expression, but this effect was attenuated by resveratrol via the activation of PPARα and PPARγ signaling. We verified that the activation of PPARα and PPARγ by WY14643 and pioglitazone, respectively, attenuated oleate triggered total FFA and TG accumulation in macrophages by repressing FFA import via the suppression of Fatp1 expression. Furthermore, the inhibition of Fatp1 by tumor necrosis factor α alleviated oleate-induced total FFA and TG accumulation in macrophages. This study provided the first demonstration that accumulation of amino acids, nucleosides, lactate, monoacylglycerols, total FFAs, and TGs in oleate-treated macrophages is effectively attenuated or even abolished by resveratrol, and that the activation of PPARα and PPARγ attenuates oleate-induced total FFA and TG accumulation via suppression of Fatp1 expression in macrophages. Therapeutic strategies aim to activate PPAR signaling, and to repress FFA import and triglyceride synthesis are promising approaches to reduce the risk of obesity, diabetes and atherosclerosis.
机译：巨噬细胞的脂质积累与微环境信号相互作用并加速糖尿病动脉粥样硬化。然而，没有清楚地理解巨噬细胞代谢与微环境信号相互作用的分子机制。因此，使用未明确的代谢组学方法来表征代谢重编程，并鉴定巨大的巨噬细胞脂质积累的潜在调节靶标，这是一种重要的营养素。代谢组种方法揭示了在油酸处理的巨噬细胞中多种代谢途径受到显着扰乱。我们发现氨基酸，核苷，乳酸盐，单酰基甘油，累积在芦e治疗的巨噬细胞中累积的总游离脂肪酸（FFA）和甘油三酯（TGS），但这些效应得到了经过白藜芦醇的经济衰减或甚至废除。值得注意的是，1-单烯烯酰基甘油和2-单烯氢甘油显示出差分代谢物中水平的最大倍数变化。随后，我们发现通过激活FORP1表达，通过加速FFA流量来引发巨噬细胞的总FFA和TG积累，但通过激活PPARα和PPARγ信号传导，通过白藜芦醇衰减这种效果。通过抑制FFA进口，通过抑制FORP1表达，通过抑制FFA导入，分别通过14643和吡格列唑和吡格列酮激活PPARα和PPARγ的激活，衰减的油脂在巨噬细胞中触发总FFA和TG积累。此外，通过肿瘤坏死因子α缓解油脂诱导的总FFA和TG积累的抑制巨噬细胞。本研究提供了第一演示，即氨基酸，核苷，乳酸盐，单酰基甘油，总FFA和Tgs的累积有效地衰减或甚至被白藜芦醇减毒，并且PPARα和PPARγ的激活衰减了油eate诱导的总量通过抑制巨噬细胞的FATP1表达的FFA和TG积累。治疗策略目的是激活PPAR信号，并抑制FFA进口和甘油三酯合成是有希望降低肥胖，糖尿病和动脉粥样硬化的风险的方法。

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