Characterization of the role of PAI-1 in lipid metabolism

PAI-1 在脂质代谢中的作用表征

• 批准号: 8247042
• 负责人: Daniel A Lawrence
• 金额: $ 22.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247042
• 关键词: Acute Disease; Adipocytes; Adipose tissue; Affect; Affinity; Antigens; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins A; Arterial Fatty Streak; Atherosclerosis; Attenuated; Binding; Biological; Biology; Blood Vessels; Body Weight; Cardiovascular Diseases; Catabolism; Cells; Central obesity; Cholesterol Homeostasis; Chronic Disease; Coculture Techniques; Complex; Data; Development; Disease; Disease Progression; Dyslipidemias; Endothelial Cells; Enzymes; Fatty acid glycerol esters; Fibrinolysis; Foam Cells; Functional disorder; Genetic; High Density Lipoproteins; Hormones; Human; Hypertension; Inflammation; Insulin Resistance; Knock-in Mouse; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Leptin; Link; Lipids; Lipoprotein Binding; Lipoproteins; Metabolic; Metabolic Pathway; Metabolic syndrome; Molecular; Molecular Conformation; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathology; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Plasma; Plasminogen Activator; Plasminogen Activator Inhibitor 1; Play; Probability; Process; Proteins; Regulation; Role; Sepsis; Suggestion; Syndrome; System; Testing; Thrombosis; Tissues; Transgenic Mice; Vascular Diseases; Very low density lipoprotein; Visceral; Vitronectin; Work; base; cell motility; cytokine; design; diabetic; hypercholesterolemia; improved; in vivo; inhibitor/antagonist; insight; lipid metabolism; macrophage; novel; novel therapeutic intervention; particle; receptor; reverse cholesterol transport; small molecule; thrombolysis; uptake

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.

高 PAI-1 水平与败血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 表明 PAI-1 可能有助于疾病的病理学。然而，PAI-1 的机制作用 PAI-1 在疾病发展中的作用尚不清楚，并且可能很复杂，因为 PAI-1 可以通过多种方式发挥作用 途径，例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 PAI-1 在从正常血管到脂肪条纹再到动脉粥样硬化的疾病进展过程中表达增加 牌匾。 PAI-1 表达增加也与肥胖和胰岛素抵抗有关，并且存在直接影响 人类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，进而导致全身性 PAI-1 升高 通过增加血栓形成而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，PAI-1 也可能在肥胖中发挥直接作用，因为 遗传性肥胖和糖尿病的 ob/ob 小鼠与 PAI-1 缺陷背景下的小鼠相比，具有显着的 与使用 PAI-1 的 ob/ob 小鼠相比，体重减轻并改善了代谢特征。同样地， 营养引起的肥胖和胰岛素抵抗已被证明在 PAI-1 null 中显着减弱 小鼠，以及用 PAI-1 抑制剂治疗的小鼠。然而，这种影响的具体机制尚不清楚 显示。这些观察结果表明 PAI-1 可能以以前未被识别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 PAI-1 在此过程中作用的分子机制。具体来说，假设 PAI-1 在脂质代谢中发挥着以前未被认识到的作用，这可能与其作为脂质代谢的作用无关。 将测试纤溶抑制剂。 PAI-1 和参与脂质代谢的蛋白质之间的新相互作用 将研究 PAI-1 的遗传和药理失活对通路的影响 将研究血浆胆固醇稳态。总之，这些研究可能会提供潜在的见解 在各种环境下的新颖治疗干预措施，包括肥胖、高胆固醇血症、 代谢综合征和心血管疾病。