Department of Internal Medicine, Division of Endocrinology, Clinical Nutrition, and Vascular Medicine, University of California, Davis, California;
Am J Physiol Heart Circ Physiol. 2014 Jan 1;306(1):H109-20. doi: 10.1152/ajpheart.00137.2013. Epub 2013 Oct 25.
Postprandial lipemia is characterized by a transient increase in circulating triglyceride-rich lipoproteins such as very low-density lipoprotein (VLDL) and has been shown to activate monocytes in vivo. Lipolysis of VLDL releases remnant particles, phospholipids, monoglycerides, diglycerides, and fatty acids in close proximity to endothelial cells and monocytes. We hypothesized that postprandial VLDL lipolysis products could activate and recruit monocytes by increasing monocyte expression of proinflammatory cytokines and adhesion molecules, and that such activation is related to the development of lipid droplets. Freshly isolated human monocytes were treated with VLDL lipolysis products (2.28 mmol/l triglycerides + 2 U/ml lipoprotein lipase), and monocyte adhesion to a primed endothelial monolayer was observed using a parallel plate flow chamber coupled with a CCD camera. Treated monocytes showed more rolling and adhesion than controls, and an increase in transmigration between endothelial cells. The increased adhesive events were related to elevated expression of key integrin complexes including Mac-1 [α(m)-integrin (CD11b)/β2-integrin (CD18)], CR4 [α(x)-integrin (CD11c)/CD18] and VLA-4 [α4-integrin (CD49d)/β1-integrin (CD29)] on treated monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) and THP-1 monocytes with VLDL lipolysis products increased expression of TNFα, IL-1β, and IL-8 over controls, with concurrent activation of NFkB and AP-1. NFκB and AP-1-induced cytokine and integrin expression was dependent on ERK and Akt phosphorylation. Additionally, fatty acids from VLDL lipolysis products induced ERK2-dependent lipid droplet formation in monocytes, suggesting a link to inflammatory signaling pathways. These results provide novel mechanisms for postprandial monocyte activation by VLDL lipolysis products, suggesting new pathways and biomarkers for chronic, intermittent vascular injury.
餐后血脂血症的特征是循环中富含甘油三酯的脂蛋白（如极低密度脂蛋白 [VLDL]）的短暂增加，并已被证明可在体内激活单核细胞。VLDL 的脂解释放出残粒、磷脂、单甘油酯、二甘油酯和脂肪酸，与内皮细胞和单核细胞非常接近。我们假设餐后 VLDL 脂解产物可以通过增加单核细胞促炎细胞因子和粘附分子的表达来激活和募集单核细胞，并且这种激活与脂滴的形成有关。新鲜分离的人单核细胞用 VLDL 脂解产物（2.28mmol/L 甘油三酯+2U/ml 脂蛋白脂肪酶）处理，并用平行板流动室和 CCD 相机观察单核细胞对预先激活的内皮单层的粘附。与对照组相比，处理后的单核细胞显示出更多的滚动和粘附，并且在细胞间迁移增加。增加的粘附事件与关键整合素复合物的表达升高有关，包括 Mac-1[α(m)-整合素（CD11b）/β2-整合素（CD18）]、CR4[α(x)-整合素（CD11c）/CD18]和 VLA-4[α4-整合素（CD49d）/β1-整合素（CD29）]。VLDL 脂解产物处理外周血单核细胞（PBMC）和 THP-1 单核细胞后，TNFα、IL-1β 和 IL-8 的表达高于对照组，同时 NFkB 和 AP-1 被激活。NFκB 和 AP-1 诱导的细胞因子和整合素表达依赖于 ERK 和 Akt 磷酸化。此外，VLDL 脂解产物中的脂肪酸诱导单核细胞中 ERK2 依赖性脂滴形成，表明与炎症信号通路有关。这些结果为 VLDL 脂解产物诱导餐后单核细胞激活提供了新的机制，为慢性、间歇性血管损伤提供了新的途径和生物标志物。
