5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity
5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity
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DOI：
10.4049/jimmunol.0901355
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Claria, Joan
中科院分区：
文献类型：
--
作者：
Horrillo, Raquel;Gonzalez-Periz, Ana;Claria, Joan
所谓的低度炎症状态的存在被认为是脂肪组织功能障碍的关键事件，导致脂肪因子和游离脂肪酸（FFA）的分泌改变、胰岛素抵抗以及与肥胖相关的肝脏并发症的发展。本研究旨在探讨促炎性5-脂氧合酶（5-LO）通路在实验性肥胖症脂肪组织炎症和脂质功能障碍中的潜在作用。在脂肪组织以及脂肪细胞和基质血管组分中检测到5-LO途径的关键组分以及白三烯（LT）受体的组成型表达。肥胖小鼠的脂肪组织，与瘦小鼠相比，表现出增加5-LO激活蛋白（FLAP）的表达和LTB 4水平。用5-LO产物孵育脂肪组织导致NF-κ B活化和促炎脂肪因子如MCP-1、IL-6和TNF-α的分泌增加。此外，LTB 4，而不是LTD 4，减少原代脂肪细胞的FFA摄取，而5-LO抑制抑制异丙肾上腺素诱导的脂肪组织脂解。在饮食性肥胖的小鼠中，脂肪组织中FLAP表达升高与巨噬细胞浸润、循环FFA水平升高和肝脂肪变性相关，这些现象通过用Bay-X-1005抑制FLAP而逆转。有趣的是，FLAP抑制诱导AMP激活的蛋白激酶磷酸化，同时降低对脂肪酶敏感的脂肪酶活性以及TNF-α和IL-6的表达和分泌。在与Bay-X-1005或选择性LTB 4受体拮抗剂U-75302孵育的分化的3 T3-L1脂肪细胞中观察到类似的作用。综上所述，这些发现表明，5-LO途径信号脂肪组织低度炎症状态和实验性肥胖的脂肪生成潜力。免疫学杂志，2010，184：3978-3987。
The presence of the so-called low-grade inflammatory state is recognized as a critical event in adipose tissue dysfunction, leading to altered secretion of adipokines and free fatty acids (FFAs), insulin resistance, and development of hepatic complications associated with obesity. This study was designed to investigate the potential contribution of the proinflammatory 5-lipoxygenase (5-LO) pathway to adipose tissue inflammation and lipid dysfunction in experimental obesity. Constitutive expression of key components of the 5-LO pathway, as well as leukotriene (LT) receptors, was detected in adipose tissue as well as in adipocyte and stromal vascular fractions. Adipose tissue from obese mice, compared with that from lean mice, exhibited increased 5-LO activating protein (FLAP) expression and LTB4 levels. Incubation of adipose tissue with 5-LO products resulted in NF-kappa B activation and augmented secretion of proinflammatory adipokines such as MCP-1, IL-6, and TNF-alpha. In addition, LTB4, but not LTD4, reduced FFA uptake in primary adipocytes, whereas 5-LO inhibition suppressed isoproterenol-induced adipose tissue lipolysis. In mice with dietary obesity, elevated FLAP expression in adipose tissue was paralleled with macrophage infiltration, increased circulating FFA levels, and hepatic steatosis, phenomena that were reversed by FLAP inhibition with Bay-X-1005. Interestingly, FLAP inhibition induced AMP-activated protein kinase phosphorylation in parallel with decreases in hormone-sensitive lipase activity and the expression and secretion of TNF-alpha and IL-6. Similar effects were observed in differentiated 3T3-L1 adipocytes incubated with either Bay-X-1005 or the selective LTB4 receptor antagonist U-75302. Taken together, these findings indicate that the 5-LO pathway signals the adipose tissue low-grade inflammatory state and steatogenic potential in experimental obesity. The Journal of Immunology, 2010, 184: 3978-3987.