北京大学医学部生理与病理生理学系徐国恒教授的实验室，最近对阿司匹林等水杨酸类非甾体抗炎药物的新作用及其机制进行了研究，阐明了水杨酸类药物直接抑制肿瘤坏死因子α（TNFα）刺激的脂肪分解即甘油三酯水解效应，是该类药物降低血浆游离脂肪酸水平的细胞生物学基础。这一研究表明，脂肪组织是水杨酸类药物作用的有效新靶点，有助于加深对其复杂的药理作用和机制的理解。相关研究论文日前已在药理学界权威学术期刊《分子药理学》网络版发表。
早在100多年前科研人员就已发现，作为传统的非甾体抗炎药，大剂量水酸类药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浆游离脂肪酸水平。然而，随着上世纪50年代前后磺酰脲类和二甲双胍类降糖药物的出现，水杨酸类药物的降糖作用似乎逐渐被现代医学遗忘和忽视。最近几年，随着两种新开发的噻唑烷酮类抗糖尿病药物因严重的不良反应被相继撤市，经典的水杨酸类药物的胰岛素增敏和降糖作用重新引起了科研人员的关注。
近年来的研究表明，肥胖、炎症与胰岛素抵抗和糖尿病的发生发展过程密切相关。一方面，以脂肪细胞数量增多和体积增大为特征的肥胖本身即被认为是一；另一方面，正常人或处于炎症状态的患者，特别是肥胖患者的脂肪组织能产生大量的炎性因子，包括TNFα。如果说肾上腺素是刺激生理性脂肪分解的重要激素，而TNFα则是刺激脂肪分解的主要病理炎性因子。TNFα缓慢而强烈地刺激甘油三酯水解，释放出大量的游离脂肪酸进入血液循环，使血中游离脂肪酸浓度的持久性升高，进而抑制葡萄糖的利用，是导致胰岛素抵抗和糖尿病发生发展的重要因素。徐国恒教授推测，水杨酸类药物的降血糖效应，可能与其降低血浆游离脂肪酸，进而增加胰岛素的敏感性有关。然而，此类药物降低血浆脂肪酸的药理机制并不清楚。由于血浆中的游离脂肪酸主要来自脂肪组织的甘油三酯分解，他们进一步推测，水杨酸类药物降低血浆脂肪酸的药理机制可能与其抑制TNFα刺激的甘油三酯水解有关。
徐国恒教授领导研究人员在大鼠成熟脂肪细胞上详细研究了水杨酸钠对TNFα刺激的脂肪分解的影响及其分子机制。结果表明，在临床抗炎治疗剂量范内，水杨酸钠能剂量和时间依赖性抑制TNFα刺激的甘油三酯水解，抑制游离脂肪酸由脂肪组织向血液循环的释放。在分子水平上，水杨酸钠这一作用的机制与其抑制细胞外信号调节激酶ERK的磷酸化和抑制脂肪细胞内cAMP增加有关。油滴包被蛋白perilipin是调节脂肪分解的双向分子开关，TNFα可通过下调perilipin并增加perilipin蛋白磷酸化而刺激甘油三酯水解；水杨酸盐则完全阻断了这些效应。更进一步发现，水杨酸盐虽然并不改变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。不仅如此，水杨酸钠既能降低基础脂肪分解，又能阻断高浓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浆游离脂肪酸浓度，增加胰岛素敏感性，这一作用在糖尿病患者全身组织细胞处于高浓度葡萄糖的环境下具有重要意义。
这项研究从新的角度阐述了阿司匹林类药物降低血浆游离脂肪酸和增加素敏感性的细胞分子通路和机制，为进一步认识阿司匹林类药物的新靶点和拓宽其临床应用提供了新的资料。（中国医药报）
原始出处:
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: xug@bjmu.edu.cn
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
