北京大學(xué)醫(yī)學(xué)部生理與病理生理學(xué)系徐國恒教授的實(shí)驗(yàn)室,，最近對阿司匹林等水楊酸類非甾體抗炎藥物的新作用及其機(jī)制進(jìn)行了研究，闡明了水楊酸類藥物直接抑制腫瘤壞死因子α（TNFα）刺激的脂肪分解即甘油三酯水解效應(yīng),，是該類藥物降低血漿游離脂肪酸水平的細(xì)胞生物學(xué)基礎(chǔ),。這一研究表明，脂肪組織是水楊酸類藥物作用的有效新靶點(diǎn),，有助于加深對其復(fù)雜的藥理作用和機(jī)制的理解,。相關(guān)研究論文日前已在藥理學(xué)界權(quán)威學(xué)術(shù)期刊《分子藥理學(xué)》網(wǎng)絡(luò)版發(fā)表。
早在100多年前科研人員就已發(fā)現(xiàn),，作為傳統(tǒng)的非甾體抗炎藥，大劑量水酸類藥物能有效降低糖尿病患者的尿糖和血糖,，并降低正常人和糖尿病患者的血漿游離脂肪酸水平,。然而，隨著上世紀(jì)50年代前后磺酰脲類和二甲雙胍類降糖藥物的出現(xiàn),，水楊酸類藥物的降糖作用似乎逐漸被現(xiàn)代醫(yī)學(xué)遺忘和忽視,。最近幾年，隨著兩種新開發(fā)的噻唑烷酮類抗糖尿病藥物因嚴(yán)重的不良反應(yīng)被相繼撤市,，經(jīng)典的水楊酸類藥物的胰島素增敏和降糖作用重新引起了科研人員的關(guān)注,。
近年來的研究表明,，肥胖、炎癥與胰島素抵抗和糖尿病的發(fā)生發(fā)展過程密切相關(guān),。一方面,，以脂肪細(xì)胞數(shù)量增多和體積增大為特征的肥胖本身即被認(rèn)為是一；另一方面,，正常人或處于炎癥狀態(tài)的患者,，特別是肥胖患者的脂肪組織能產(chǎn)生大量的炎性因子，包括TNFα,。如果說腎上腺素是刺激生理性脂肪分解的重要激素,，而TNFα則是刺激脂肪分解的主要病理炎性因子。TNFα緩慢而強(qiáng)烈地刺激甘油三酯水解,，釋放出大量的游離脂肪酸進(jìn)入血液循環(huán),，使血中游離脂肪酸濃度的持久性升高，進(jìn)而抑制葡萄糖的利用,，是導(dǎo)致胰島素抵抗和糖尿病發(fā)生發(fā)展的重要因素,。徐國恒教授推測，水楊酸類藥物的降血糖效應(yīng),，可能與其降低血漿游離脂肪酸,，進(jìn)而增加胰島素的敏感性有關(guān)。然而,，此類藥物降低血漿脂肪酸的藥理機(jī)制并不清楚,。由于血漿中的游離脂肪酸主要來自脂肪組織的甘油三酯分解，他們進(jìn)一步推測,，水楊酸類藥物降低血漿脂肪酸的藥理機(jī)制可能與其抑制TNFα刺激的甘油三酯水解有關(guān),。
徐國恒教授領(lǐng)導(dǎo)研究人員在大鼠成熟脂肪細(xì)胞上詳細(xì)研究了水楊酸鈉對TNFα刺激的脂肪分解的影響及其分子機(jī)制。結(jié)果表明,，在臨床抗炎治療劑量范內(nèi),，水楊酸鈉能劑量和時(shí)間依賴性抑制TNFα刺激的甘油三酯水解，抑制游離脂肪酸由脂肪組織向血液循環(huán)的釋放,。在分子水平上,，水楊酸鈉這一作用的機(jī)制與其抑制細(xì)胞外信號調(diào)節(jié)激酶ERK的磷酸化和抑制脂肪細(xì)胞內(nèi)cAMP增加有關(guān)。油滴包被蛋白perilipin是調(diào)節(jié)脂肪分解的雙向分子開關(guān),，TNFα可通過下調(diào)perilipin并增加perilipin蛋白磷酸化而刺激甘油三酯水解,；水楊酸鹽則完全阻斷了這些效應(yīng)。更進(jìn)一步發(fā)現(xiàn),，水楊酸鹽雖然并不改變脂肪水解酶的蛋白水平,，但能有效抑制TNFα升高的脂肪酶活性。不僅如此,，水楊酸鈉既能降低基礎(chǔ)脂肪分解,，又能阻斷高濃度葡萄糖本身刺激的甘油三酯水解,。因其有助于降低糖尿病患者的血漿游離脂肪酸濃度，增加胰島素敏感性,，這一作用在糖尿病患者全身組織細(xì)胞處于高濃度葡萄糖的環(huán)境下具有重要意義,。
這項(xiàng)研究從新的角度闡述了阿司匹林類藥物降低血漿游離脂肪酸和增加素敏感性的細(xì)胞分子通路和機(jī)制，為進(jìn)一步認(rèn)識阿司匹林類藥物的新靶點(diǎn)和拓寬其臨床應(yīng)用提供了新的資料,。（中國醫(yī)藥報(bào)）
原始出處:
Molecular Pharmacology Fast Forward
First published on October 2, 2007; DOI: 10.1124/mol.107.039479
Received for publication July 2, 2007.
Revised September 26, 2007.
Accepted for publication October 2, 2007.
Salicylate Blocks Lipolytic Actions of Tumor Necrosis Factor-TNF- in Primary Rat Adipocytes
Luxia Zu 1, Hongfeng Jiang 1, Jinhan He 1, Chong Xu 1, Shenshen Pu 1, Meifang Liu 1, Guoheng Xu 1*
1 Peking University Health Science Center
* Address correspondence to: E-mail: [email protected]
Abstract
Increased systemic free fatty acids (FFA) impair insulin sensitivity. In obese and diabetic subjects, production of a proinflammatory cytokine, tumor necrosis factor- (TNF-), is elevated. TNF- has a variety of effects by inducing inflammation, decreasing glucose utilization, and also stimulating adipocyte lipolysis to release FFA to plasma. High doses of nonsteroidal anti-inflammatory drug salicylates have been long recognized to lower blood FFA and glucose in humans, although the mechanisms are not fully understood. In this report, we show that sodium salicylate at therapeutic concentrations directly blocks TNF--stimulated lipolysis and therefore inhibits FFA release from primary rat adipocytes. To elucidate the cellular basis of this action, we show that salicylate suppresses TNF--induced extracellular signal-related kinase activation and intracellular cAMP elevation, two early events during the lipolysis response to TNF-. Further, salicylate prevents the downregulation of cyclic-nucleotide phosphodiesterase 3B, an enzyme responsible for cAMP hydrolysis. Perilipins coat intracellular lipid droplet surface by restricting lipase access to the triacylglycerol substrates. TNF- downregulates perilipin but promotes its phosphorylation during lipolysis stimulation; these actions are efficiently reversed by salicylate. Salicylate slightly reduces basal but completely inhibits TNF--liberated lipase activity. In contrast, neither salicylate nor TNF- alters the protein levels of hormone-sensitive lipase and adipose triglyceride lipase. In addition, sodium salicylate restricts basal lipolysis simulated by a high concentration of glucose and significantly diminishes the high glucose-enhanced lipolysis response to TNF-. These results provide novel evidence that salicylate directly blocks TNF--mediated FFA efflux from adipocytes, hence reducing plasma FFA levels and increasing insulin sensitivity.
Key words: Tumor necrosis factor, cAMP, Protein Kinase A, MAP Kinase
