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CPT1a gene expression reverses the inflammatory and anti-phagocytic effect of 7-ketocholesterol in RAW264.7 macrophages.
Lipids in Health and Disease ( IF 4.5 ) Pub Date : 2019-12-10 , DOI: 10.1186/s12944-019-1156-7
Priscila Calle 1 , Angeles Muñoz 1 , Anna Sola 2, 3 , Georgina Hotter 1, 3
Affiliation  

BACKGROUND Macrophage are specialized cells that contributes to the removal of detrimental contents via phagocytosis. Lipid accumulation in macrophages, whether from phagocytosis of dying cells or from circulating oxidized low-density lipoproteins, alters macrophage biology and functionality. It is known that carnitine palmitoyl transferase 1-a (CPT1a) gene encodes an enzyme involved in fatty acid oxidation and, therefore, lipid content. However, the potential of CPT1a to activate macrophage phagocytic function have not been elucidated. METHODS Using a murine macrophage cell line, RAW264.7, we determine if intracellular accumulation of 7-ketocholesterol (7-KC) modulates macrophage phagocytic function through CPT1a gene expression. In addition, the effects of CPT1a genetic modification on macrophage phenotype and phagocytosis has been studied. RESULTS Our results revealed that CPT1a gene expression decreased by the accumulation of 7-KC at the higher dose of 7-KC. This was concomitant with an impair ability to phagocytize bioparticles and an inflammatory phenotype. GW3965 treatment, which have shown to facilitate the efflux of cholesterol, eliminated the intracellular lipid droplets of 7-KC-laden macrophages, increased the gene expression of CPT1a, diminished the gene expression of the inflammatory marker iNOS and restored macrophage phagocytosis. Furthermore, CPT1a Knockdown per se was detrimental for macrophage phagocytosis whereas transcriptional activation of CPT1a heightened the uptake of bioparticles. CONCLUSIONS Altogether, our findings indicate that downregulation of CPT1a by lipid content modulates macrophage phagocytosis and inflammatory phenotype.

中文翻译:

CPT1a基因表达逆转了RAW264.7巨噬细胞中7-酮胆固醇的炎症和抗吞噬作用。

背景技术巨噬细胞是专门细胞,其通过吞噬作用有助于去除有害内容物。无论是来自垂死细胞的吞噬作用还是来自循环的氧化型低密度脂蛋白,巨噬细胞中的脂质蓄积都会改变巨噬细胞的生物学和功能。众所周知,肉碱棕榈酰转移酶1-a(CPT1a)基因编码一种参与脂肪酸氧化并因此参与脂质含量的酶。但是,尚未阐明CPT1a激活巨噬细胞吞噬功能的潜力。方法使用鼠类巨噬细胞RAW264.7,我们确定细胞内7-酮胆固醇(7-KC)的积累是否通过CPT1a基因表达调节巨噬细胞的吞噬功能。另外,已经研究了CPT1a基因修饰对巨噬细胞表型和吞噬作用的影响。结果我们的结果表明,在较高剂量的7-KC时7-KC的积累会降低CPT1a基因的表达。这伴随着吞噬生物颗粒的能力受损和发炎表型。GW3965治疗已显示出促进胆固醇外流的作用,它消除了载有7-KC的巨噬细胞的细胞内脂质滴,增加了CPT1a的基因表达,减少了炎性标志物iNOS的基因表达并恢复了巨噬细胞的吞噬作用。此外,CPT1a的敲除本身对巨噬细胞的吞噬作用是有害的,而CPT1a的转录激活则增加了生物颗粒的摄取。结论总之,我们的发现表明脂质含量对CPT1a的下调可调节巨噬细胞的吞噬作用和炎性表型。
更新日期:2019-12-10
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