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.
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