長(zhǎng)期以來，臨床上發(fā)現(xiàn)細(xì)菌感染伴隨著血漿游離脂肪酸升高,。脂肪酸升高不僅為細(xì)菌感染和發(fā)燒的機(jī)體提供必要的能量物質(zhì),，也損害糖尿病病人的胰島素敏感性。一般認(rèn)為,，腎上腺素是細(xì)菌感染時(shí)體內(nèi)刺激脂肪分解的主要激素,。
不過，北京大學(xué)醫(yī)學(xué)部生理與病理生理學(xué)系徐國恒教授以及俎魯霞博士近日在國際著名期刊《生物化學(xué)雜志》(JBC)網(wǎng)絡(luò)版發(fā)表的論文卻提出了新的解釋,。
他們發(fā)現(xiàn),，革蘭氏陰性菌細(xì)胞壁上的脂多糖成分———內(nèi)毒素，可直接刺激脂肪細(xì)胞甘油三酯水解釋放游離脂肪酸,。這種水解,，主要是通過脂肪細(xì)胞TLR4和ERK信號(hào)介導(dǎo)的，在TLR4缺陷動(dòng)物和脂肪細(xì)胞,，內(nèi)毒素不再能夠刺激甘油三酯水解和升高血漿游離脂肪酸。
徐國恒教授的這項(xiàng)基礎(chǔ)與臨床相結(jié)合的研究,，表明脂肪細(xì)胞也是細(xì)菌內(nèi)毒素的直接靶標(biāo),，揭示了細(xì)菌內(nèi)毒素刺激脂肪細(xì)胞甘油三酯水解的作用及其機(jī)制,，為革蘭氏細(xì)菌感染病人血漿游離脂肪酸升高和胰島素抵抗等臨床現(xiàn)象的發(fā)生機(jī)理，提供了新的解釋,。
據(jù)了解,，該研究由國家自然科學(xué)基金資助完成。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
