Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation

Adipose tissue has recently been reevaluated as an endocrine organ, and adipose‐tissue‐derived endocrine factors are termed adipokines. Plasminogen activator inhibitor‐1 (PAI‐1) is the primary inhibitor of PAs, which convert plasminogen into plasmin, a critical protease involved in fibrinolysis. PAI‐1 induces fibrinogenesis by suppressing intravascular and tissue fibrinolysis. Moreover, PAI‐1 exerts various cellular effects independently of fibrinolysis. Although PAI‐1 is expressed in various tissues, its expression is regulated by numerous growth factors, cytokines, and hormones in a paracrine and endocrine manner. Adipocyte‐derived PAI‐1, predominantly expressed in visceral fat, is released into the circulation in parallel with increased fat mass, and it functions as a crucial adipokine that negatively affects physiological metabolism and vascular biology. Elevated PAI‐1 levels induce insulin resistance and metabolic abnormalities during proinflammatory processes involving several cytokines and chemokines in diabetes. Several studies have indicated that PAI‐1 plays crucial roles in insulin actions on liver, muscle, and fat. Accumulated fat and enhanced adipose tissue‐derived PAI‐1 influence metabolism and vessels in relation to macrophage infiltration, chronic inflammation, and free fatty acid release in obese states. PAI‐1‐induced fibrinolysis abnormalities are associated with metabolic syndrome, leading to cardiovascular disease through dysregulated vascular coagulation, endothelial dysfunction, and metabolic abnormalities. Adipose tissue‐derived PAI‐1 is involved in insulin resistance, osteoporosis, and sarcopenia induced by glucocorticoid excess in mice. Moreover, PAI‐1 is involved in the other pathological states, such as nonalcoholic fatty liver disease, and cancer. As such, PAI‐1 may be exploited as a marker of disease activity as well being a target for clinical drug development.