Characterization of the role of PAI-1 in lipid metabolism

高派-1水平与急性疾病如脓毒症和慢性疾病有关 包括动脉粥样硬化和2型糖尿病。派-1与这些综合征的相关性导致了 提示派-1可能参与疾病的病理过程。然而，派-1的机制作用， 在疾病发展中的作用尚不清楚，并且可能是复杂的，因为派-1可以通过多种途径起作用。 途径，如通过调节纤溶酶原激活剂来调节纤维蛋白溶解，或通过影响 通过细胞迁移的直接调节进行组织重塑。在心血管疾病中，血管派-1 从正常血管到脂肪条纹，再到动脉粥样硬化， 斑块派-1表达增加也与肥胖和胰岛素抵抗有关， 人和小鼠内脏脂肪量与血浆派-1水平之间的相关性。这 这表明脂肪组织本身可能直接导致全身派-1升高，这反过来又 通过增加血栓形成增加血管疾病的可能性，并加速 动脉粥样硬化然而，最近的数据表明，派-1也可能在肥胖中发挥直接作用，因为 遗传肥胖和糖尿病ob/ob小鼠与派-1缺陷背景杂交， 与具有派-1的ob/ob小鼠相比，体重减轻并且代谢谱改善。同样地， 营养诱导的肥胖和胰岛素抵抗在派-1缺失的人中已显示出显著减弱， 小鼠和用派-1抑制剂治疗的小鼠中。然而，这种影响的确切机制并不清楚。 示出了这些观察结果表明派-1可能以以前未被认识的方式与通路相互作用， 参与调节肥胖和脂质代谢。因此，本申请中概述的研究旨在 了解派-1在此过程中的分子机制。具体来说，假设 派-1在脂质代谢中起着以前未被认识到的作用，这可能与其作为脂质代谢抑制剂的作用无关。 将测试纤维蛋白溶解抑制剂。派-1与脂质代谢相关蛋白的新型相互作用 将研究派-1的遗传和药理学失活的影响， 将研究血浆胆固醇稳态。总之，这些研究可以提供潜在的洞察力， 在各种情况下，包括肥胖症，高胆固醇血症， 代谢综合征和心血管疾病。

High PAI-1 levels have been associated with both acute diseases such as sepsis and with chronic disorders including atherosclerosis and type 2 diabetes. The association of PAI-1 with these syndromes has led to the suggestion that PAI-1 may contribute to the pathology of disease. However, the mechanistic role that PAI-1 plays in disease development is not clear and is likely to be complex since PAI-1 can act through multiple pathways, such as modulating fibrinolysis through the regulation of plasminogen activators, or by influencing tissue remodeling through the direct regulation of cell migration. In cardiovascular disease, vascular PAI-1 expression increases during disease progression from normal vessels, to fatty streaks, to atherosclerotic plaques. Increased PAI-1 expression is also linked to obesity, and insulin resistance, and there is a direct correlation between the amount of visceral fat and plasma levels of PAI-1 in both humans and mice. This has lead to the suggestion that adipose tissue itself may directly contribute to elevated systemic PAI-1, which inturn increases the probability of vascular disease through increased thrombosis, and accelerated atherosclerosis. However, very recent data suggests that PAI-1 may also play a direct role in obesity since genetically obese and diabetic ob/ob mice crossed into a PAI-1 deficient background have significantly reduced body weight and improved metabolic profiles compared to ob/ob mice with PAI-1. Likewise, nutritionally-induced obesity and insulin resistance have been shown to be markedly attenuated in PAI-1 null mice, and in mice treated with a PAI-1 inhibitor. However, the precise mechanism of this affect was not shown. These observations suggest that PAI-1 may interact in previously unrecognized ways with pathways involved in regulating obesity and lipid metabolism. Thus, the studies outlined in this application are aimed at understanding of the molecular mechanisms of PAI-1 s role in this process. Specifically, the hypothesis that PAI-1 plays a previously unrecognized role in lipid metabolism that may be unrelated to its role as a fibrinolytic inhibitor will be tested. Novel interactions between PAI-1 and proteins involved in lipid metabolic pathways will be studied, and the effects of both genetic and pharmacological inactivation of PAI-1 on plasma cholesterol homeostasis will be studied. Together, these studies may provide potential insight into novel therapeutic interventions in a wide variety of settings, including obesity, hypercholesterolemia, metabolic syndrome, and cardiovascular disease.