Characterization of the role of PAI-1 in lipid metabolism

PAI-1水平升高与脓毒症等急性疾病和慢性疾病有关。 包括动脉粥样硬化和2型糖尿病。PAI-1与这些综合征的关联导致了 提示PAI-1可能参与了疾病的病理过程。然而，PAI-1的机械作用 PAI-1在疾病发展中的作用尚不清楚，而且可能是复杂的，因为PAI-1可以通过 途径，如通过调节纤溶酶原激活剂或通过影响 通过直接调节细胞迁移来进行组织重塑。在心血管疾病中，血管性纤溶酶原激活物-1 在疾病从正常血管到脂肪条纹，再到动脉粥样硬化的过程中，表达增加 斑块。PAI-1表达增加也与肥胖、胰岛素抵抗有关，而且有直接的 人和小鼠内脏脂肪量与血浆PAI-1水平之间的相关性。这有 导致脂肪组织本身可能直接导致全身性PAI-1升高，进而 通过增加血栓形成增加血管疾病的可能性，并加速 动脉硬化。然而，最近的数据表明，PAI-1也可能在肥胖中发挥直接作用，因为 遗传肥胖和糖尿病的ob/ob小鼠交叉进入PAI-1缺乏背景的显著 与使用PAI-1的ob/ob小鼠相比，减轻了体重并改善了代谢特征。同样， 营养诱导的肥胖和胰岛素抵抗已经被证明在PAI-1缺失的情况下显著减轻 小鼠，以及用PAI-1抑制剂处理的小鼠。然而，这种影响的确切机制并不是 展示了。这些观察表明，PAI-1可能以以前未知的方式与通路相互作用 参与调节肥胖和脂类代谢。因此，本申请中概述的研究旨在 了解纤溶酶原激活物-1的分子机制S在这一过程中的作用。具体地说，假设 PAI-1在脂代谢中发挥着以前未被认识到的作用，这可能与其作为一种 纤溶抑制物将进行测试。纤溶酶原激活物-1与脂代谢相关蛋白的新相互作用 将研究PAI-1的途径，以及PAI-1的遗传和药物失活对 将研究血浆胆固醇的动态平衡。总而言之，这些研究可能为我们提供潜在的洞察 各种环境下的新型治疗干预措施，包括肥胖、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.