Qiu Guosong, Ho Alexander C, Yu Willie, Hill John S
St. Paul's Hospital, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
J Lipid Res. 2007 Feb;48(2):385-94. doi: 10.1194/jlr.M600304-JLR200. Epub 2006 Nov 8.
LPL and endothelial lipase (EL) are associated with macrophages in human atherosclerotic lesions, and overexpression of LPL in mouse macrophages is associated with a greater extent of atherosclerosis. To investigate potential mechanisms by which macrophage-derived lipase expression may mediate proatherogenic effects, we used lentivirus-mediated RNA interference to suppress the expression of either LPL or EL within THP-1 macrophages. After suppression of either LPL or EL, significant decreases in the concentration of interleukin-1beta, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha were observed. Incubation of THP-1 macrophages with either mildly or extensively oxidized LDL consistently decreased cytokine expression, which was additive to that contributed by lipase suppression. Decreased lipase expression was also associated with an altered lipid composition, with reduced percentages of cholesterol (unesterified and esterified), triglycerides, and lysophosphatidylcholine. Microarray data indicated a decreased expression of proinflammatory genes, growth factors, and antiapoptotic genes. By contrast, there was an increased expression of lipoprotein receptors (scavenger receptor 1, low density lipoprotein receptor, scavenger receptor class B type I, and CD36). Thus, we conclude that the suppression of either LPL or EL decreases proinflammatory cytokine expression and influences the lipid composition of THP-1 macrophages. These results provide further insight into the specific metabolic and potential pathological roles of LPL and EL in human macrophages.
脂蛋白脂肪酶（LPL）和内皮脂肪酶（EL）与人动脉粥样硬化病变中的巨噬细胞相关，并且小鼠巨噬细胞中LPL的过表达与动脉粥样硬化程度加重有关。为了研究巨噬细胞源性脂肪酶表达可能介导促动脉粥样硬化作用的潜在机制，我们使用慢病毒介导的RNA干扰来抑制THP-1巨噬细胞中LPL或EL的表达。抑制LPL或EL后，观察到白细胞介素-1β、白细胞介素-6、单核细胞趋化蛋白-1和肿瘤坏死因子-α的浓度显著降低。用轻度或广泛氧化的低密度脂蛋白孵育THP-1巨噬细胞持续降低细胞因子表达，这与脂肪酶抑制作用相加。脂肪酶表达降低还与脂质组成改变有关，胆固醇（未酯化和酯化）、甘油三酯和溶血磷脂酰胆碱的百分比降低。微阵列数据表明促炎基因、生长因子和抗凋亡基因的表达降低。相比之下，脂蛋白受体（清道夫受体1、低密度脂蛋白受体、B类I型清道夫受体和CD36）的表达增加。因此，我们得出结论，抑制LPL或EL可降低促炎细胞因子表达并影响THP-1巨噬细胞的脂质组成。这些结果进一步深入了解了LPL和EL在人类巨噬细胞中的特定代谢和潜在病理作用。
