Kralisch Susan, Klein Johannes, Lossner Ulrike, Blüher Matthias, Paschke Ralf, Stumvoll Michael, Fasshauer Mathias
University of Leipzig, Department of Internal Medicine III, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
Mol Cell Endocrinol. 2006 Jul 11;253(1-2):56-62. doi: 10.1016/j.mce.2006.04.027. Epub 2006 May 19.
Various adipocytokines have been described which influence insulin sensitivity and vascular function profoundly and might, therefore, potentially link obesity, insulin resistance, and atherosclerosis. Among those, plasminogen activator inhibitor (PAI)-1 is an adipose-secreted factor upregulated in obesity and insulin resistance that inhibits fibrinolysis. Furthermore, recent studies in knockout mice suggest that PAI-1 directly impairs insulin sensitivity. In the current study, the impact of growth hormone (GH) and interleukin (IL)-6 on PAI-1 mRNA synthesis and secretion was determined in 3T3-L1 adipocytes. Interestingly, 500 ng/ml GH and 30 ng/ml IL-6 increased PAI-1 secretion five-fold and 3.6-fold, respectively. Furthermore, GH and IL-6 induced PAI-1 mRNA by up to 7.3-fold, and 3.6-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 5 ng/ml GH and 10 ng/ml IL-6. Other insulin resistance-inducing hormones which stimulated PAI-1 synthesis included insulin, TNFalpha, and dexamethasone. Studies using pharmacological inhibitors suggested that basal and GH-induced PAI-1 synthesis were at least in part mediated by p44/42 mitogen-activated protein kinase but not janus kinase 2 and phosphatidylinositol 3-kinase. Taken together, our results show a differential regulation of PAI-1 mRNA by insulin resistance-inducing hormones including GH and IL-6.
多种脂肪细胞因子已被描述，它们对胰岛素敏感性和血管功能有深远影响，因此可能将肥胖、胰岛素抵抗和动脉粥样硬化联系起来。其中，纤溶酶原激活物抑制剂（PAI）-1是一种在肥胖和胰岛素抵抗中上调的脂肪分泌因子，可抑制纤维蛋白溶解。此外，最近对基因敲除小鼠的研究表明，PAI-1直接损害胰岛素敏感性。在本研究中，测定了生长激素（GH）和白细胞介素（IL）-6对3T3-L1脂肪细胞中PAI-1 mRNA合成和分泌的影响。有趣的是，500 ng/ml的GH和30 ng/ml的IL-6分别使PAI-1分泌增加了5倍和3.6倍。此外，GH和IL-6以时间依赖性方式分别诱导PAI-1 mRNA增加至7.3倍和3.6倍，在低至5 ng/ml GH和10 ng/ml IL-6的浓度下即可观察到显著刺激。其他诱导胰岛素抵抗的激素，如胰岛素、肿瘤坏死因子α和地塞米松，也刺激PAI-1合成。使用药理学抑制剂的研究表明，基础和GH诱导的PAI-1合成至少部分由p44/42丝裂原活化蛋白激酶介导，而不是由janus激酶2和磷脂酰肌醇3激酶介导。综上所述，我们的结果表明，包括GH和IL-6在内的诱导胰岛素抵抗的激素对PAI-1 mRNA有不同的调节作用。
