Bacterial Endotoxin Stimulates Adipose Lipolysis via Toll-Like Receptor 4 and Extracellular Signal-regulated Kinase Pathway
Bacterial Endotoxin Stimulates Adipose Lipolysis via Toll-Like Receptor 4 and Extracellular Signal-regulated Kinase Pathway
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DOI：
10.1074/jbc.m807852200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Xu, Guoheng
中科院分区：
文献类型：
--
作者：
Zu, Luxia;He, Jinhan;Xu, Guoheng
细菌内毒素/脂多糖引起炎症反应，也提高循环游离脂肪酸（FFAs）水平，损害胰岛素敏感性。长期以来，急性内毒素血症患者血清FFA升高被认为是由于内毒素失调脂质处理和反调节激素和细胞因子所致。在这里，我们研究了内毒素在啮齿动物和分离的原代脂肪细胞中的直接脂肪分解作用。内毒素增加体内脂肪组织的脂肪分解，提高循环FFA水平，诱导大鼠胰岛素抵抗，并直接刺激脂肪细胞体外慢性脂肪分解。内毒素的溶脂作用通过其脂质A片段介导，并被抗内毒素肽阻断。脂肪细胞因子的分泌和核因子κ B的激活都不参与内毒素诱导的脂肪分解。与儿茶酚胺不同，内毒素刺激脂肪分解，但不增加cAMP的产生和激活蛋白激酶A和蛋白激酶c。相反，内毒素诱导Raf-1、MEK1/2和ERK1/2磷酸化。抑制ERK1/2而不抑制JNK和p38 MAPK，内毒素刺激的脂肪分解停止。内毒素引起脂周蛋白下调和磷酸化，增加激素敏感脂肪酶和脂肪甘油三酯脂肪酶的活性和蛋白质水平，但不诱导激素敏感脂肪酶易位到细胞内脂滴。在TLR4 （toll样受体4）缺陷小鼠和脂肪细胞中，内毒素在体内和体外脂肪分解中均未增加。这些发现表明，内毒素通过脂肪细胞中的TLR4和ERK1/2信号通路刺激脂肪分解。内毒素的溶脂作用使游离脂肪酸从脂肪细胞外排到血液中，这可能是内毒素血症或革兰氏阴性细菌感染中全身游离脂肪酸升高和胰岛素抵抗的基础。
Bacterial endotoxin/lipopolysaccharide elicits inflammatory responses and also elevates circulating levels of free fatty acids (FFAs) and impairs insulin sensitivity. Serum FFA elevation in acute endotoxemia has long been thought to be due to endotoxin dysregulating lipid disposal and counterregulatory hormones and cytokines. Here, we investigated the direct lipolysis effect of endotoxin in rodents and in isolated primary adipocytes. Endotoxin increases lipolysis in vivo in adipose tissues, elevates circulating FFA level, induces insulin resistance in rats, and directly stimulates chronic lipolysis in vitro in adipocytes. The lipolytic action of endotoxin is mediated via its lipid A moiety and is blocked by anti-endotoxin peptides. Neither adipocytokine secretion nor nuclear factor-kappa B activation is involved in endotoxin-induced lipolysis. Different from catecholamine, endotoxin stimulates lipolysis without elevating cAMP production and activating protein kinase A and protein kinase C. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2. Upon inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis ceases. Endotoxin causes perilipin down-regulation and phosphorylation and increases the activity and protein levels of hormone-sensitive lipase and adipose triglyceride lipase but does not induce hormone-sensitive lipase translocation to intracellular lipid droplets. In TLR4 (Toll-like receptor 4)-deficient mice and adipocytes, endotoxin fails to increase in vivo and in vitro lipolysis. These findings suggest that endotoxin stimulates lipolysis via TLR4 and ERK1/2 signaling in adipocytes. The lipolytic action of endotoxin liberates FFA efflux from adipocytes to the bloodstream, which is a possible basis for systemic FFA elevation and insulin resistance in endotoxemia or Gram-negative bacterial infection.