长期以来,临床上发现细菌感染伴随着血浆游离脂肪酸升高。脂肪酸升高不仅为细菌感染和发烧的机体提供必要的能量物质,也损害糖尿病病人的胰岛素敏感性。一般认为,肾上腺素是细菌感染时体内刺激脂肪分解的主要激素。
不过,北京大学医学部生理与病理生理学系徐国恒教授以及俎鲁霞博士近日在国际著名期刊《生物化学杂志》(JBC)网络版发表的论文却提出了新的解释。
他们发现,革兰氏阴性菌细胞壁上的脂多糖成分———内毒素,可直接刺激脂肪细胞甘油三酯水解释放游离脂肪酸。这种水解,主要是通过脂肪细胞TLR4和ERK信号介导的,在TLR4缺陷动物和脂肪细胞,内毒素不再能够刺激甘油三酯水解和升高血浆游离脂肪酸。
徐国恒教授的这项基础与临床相结合的研究,表明脂肪细胞也是细菌内毒素的直接靶标,揭示了细菌内毒素刺激脂肪细胞甘油三酯水解的作用及其机制,为革兰氏细菌感染病人血浆游离脂肪酸升高和胰岛素抵抗等临床现象的发生机理,提供了新的解释。
据了解,该研究由国家自然科学基金资助完成。(生物谷Bioon.com)
生物谷推荐原始出处:
J. Biol. Chem, 10.1074/jbc.M807852200
Bacterial Endotoxin Stimulates Adipose Lipolysis via Toll-Like Receptor 4 and Extracellular Signal-Regulated Kinase Pathway
Luxia Zu, Jinhan He, Hongfeng Jiang, Chong Xu, Shenshen Pu, and Guoheng Xu
Department of Physiology and Pathophysiology,, Peking University Health Science Center, Beijing 100191
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 endotoxaemia has been long 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-kappaB activation is involved endotoxin-induced lipolysis. Different from catecholamine, endotoxin stimulates lipolysis without elevating cAMP production and activating protein kinase A (PKA) and PKC. Instead, endotoxin induces phosphorylation of Raf-1, MEK1/2, and ERK1/2. On inhibition of ERK1/2 but not JNK and p38 MAPK, endotoxin-stimulated lipolysis ceases. Endotoxin causes perilipin downregulation and phosphorylation and increases the activity and protein levels of hormone-sensitive lipase (HSL) and adipose triglyceride lipase but does not induce HSL translocation to intracellular lipid droplets. In Toll-like receptor 4 (TLR4)-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 endotoxaemia or Gram-negative bacterial infection.