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

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ABSTRACT

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. © 2016 American Physiological Society. Compr Physiol 6:1873‐1896, 2016.

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Figure 1. Figure 1. Fibrinolytic system. Plasminogen is converted into plasmin by tPA and uPA. Plasmin resolves the formed fibrin clots by fibrinolysis. PAI‐1 is the most important inhibitor of tPA and uPA. PAI‐1 activation suppresses fibrinolysis, resulting in enhanced fibrinogenesis. FDP, fibrin degradation products.
Figure 2. Figure 2. Fibrinolysis‐independent effects of PAI‐1PAI‐1 interacts with cell surface receptors, vitronectin, uPA/uPAR complexes, and LRP 1. Cells localize both uPA and PAI‐1 leading to the modulation of interrelated events involving extracellular matrix proteins and cell functions, such as migration, proliferation, differentiation, and apoptosis. In this reaction, uPA interacts with cell surface uPAR, and PAI‐1 binds to uPA/uPAR or vitronectin. Subsequent tissue proteolysis modulates extracellular matrix architecture and influences cell‐matrix interactions through integrin receptors and the release of bioactive factors and growth factors affecting cellular functions. LRP1 ligand binding and its complex formation with integrins, growth factor receptors, and proteoglycans induces various protein kinases. Data, with permission, from Czekay et al., Ref. .
Figure 3. Figure 3. Human PAI‐1 promoter and transcription factor binding sites. AP‐1, Activator protein 1‐like binding element; E, E‐box; FKHR, FoxO/forkhead like binding element; HRE, hypoxia response element; NBRE, NGF1‐β responsive element/Nurr77 response element; SP1, stimulatory protein‐1 response element; SRE, Smad3/4‐binding element/TGF‐β response element; VLDL‐RE, very‐low‐density lipoprotein response element. Data, with permission, from Dimova et al., Ref. .
Figure 4. Figure 4. Role of adipose tissue‐derived PAI‐1 in various diseases. Adipose tissue includes adipocytes, macrophages, and vessels. These cells participate in the production of adipokines. The accumulation of fat in adipose tissue and adipokines secreted from adipose tissue are associated with various diseases. PAI‐1 is a crucial adipokine that negatively affects physiological cellular events through mechanisms dependent on and independent of fibrinolysis. The elevations in PAI‐1, TNF‐α, IL‐1, IL‐6, MCP‐1, leptin, and free fatty acids released from adipose tissue as well as a decrease in adiponectin are related to insulin resistance, cardiovascular disease, osteoporosis, sarcopenia, senescence, and cancer. Obesity, inflammation, hypoxia, stress, and corticosteroids induce the dysregulation of adipokine secretion from adipose tissue as well as adipocyte hypertrophy. MCP‐1, monocyte chemoattractant protein‐1.
Figure 5. Figure 5. Role of adipose‐derived MCP‐1 in stress response to diabetes. The diabetes‐induced stress response is composed of two pathways via the sympathetic nervous system leading to the secretion of catecholamines and the hypothalamic‐pituitary‐adrenal axis leading to an increase in glucocorticoids. Macrophage accumulation in adipose tissue is related to the secretion of inflammatory adipokines and the release of free fatty acids related to lipolysis. This pathological modulation promotes the imbalance of glucose metabolism and the coagulation system. Acute stress induces a thrombotic tendency with increases in PAI‐1 levels derived from adipose tissues. Stress induces the production of MCP‐1 from adipose stromal cells, then enhances adipose inflammation and the secretion of proinflammatory adipokines, such as PAI‐1. These adipokines lead to procoagulatory state and insulin resistance, TNF‐α and IL‐6 enhance the production of MCP‐1 from adipocytes and endothelial cells in adipose tissue, and monocytes infiltrating into adipose tissue in response to MCP‐1 secrete TNF‐α and IL‐6. Thus, adipose tissue‐derived MCP‐1 enhances the amplification cascade during chronic inflammation in adipose tissue through autocrine and paracrine interactions among macrophages, adipocytes, and endothelial cells under stress conditions and in the diabetic state. Data, with permission, from Uchida et al., Ref. .
Figure 6. Figure 6. Role of PAI‐1 in diabetic osteoporosis in female mice. The diabetic state enhances the expression of PAI‐1 in the liver, leading to an elevation in circulating PAI‐1 levels in female mice. Then, circulating PAI‐1 suppresses osteoblast differentiation and mineralization, although it enhances adipogenesis in bone marrow tissue, resulting in diabetic osteoporosis. Data, with permission, from Tamura et al., Ref. .
Figure 7. Figure 7. Diabetes, PAI‐1, and adipose‐derived stem cells. Adipose‐derived stem cells are clinically useful for tissue repair and regeneration. Angiogenesis is important for the induction of tissue repair by adipose‐derived stem cells. PAI‐1 levels from adipose‐derived stromal cells are elevated in patients with diabetes, leading to a decrease in angiogenic activity by adipose‐derived stromal cells. Adipose tissue‐derived PAI‐1 might limit the angiogenic activity during tissue repair and regeneration by adipose‐derived stem cells in diabetes. PAI‐1 affects uPA that induces the production of plasmin by the cleavage of plasminogen and the activation of MMPs and growth factors in tissue as well as an activation of urokinase plasminogen activator receptor (uPAR) on the cell surface. This uPA system is important for the migration and invasion of vascular endothelial cells as well as the maintenance of an adequate cell microenvironment during tissue repair. An elevation in circulating and tissue PAI‐1 expression in diabetes may contribute to a decrease in fibrinolytic activity of adipose‐derived stem cells as well as in the cell microenvironment during tissue repair. Data, with permission, from Acosta et al., Ref. ; Dzhoyashvili et al., Ref. ; and Tashiro et al., Ref. . VEGF, vascular endothelial growth factor.
Figure 8. Figure 8. The mechanism by which obesity induces proinflammatory adipokines. Obesity induced by excessive food intake is characterized by the chronic and excessive accumulation of fat and subsequent metabolic disorders with low‐intensity chronic inflammation, resulting in insulin resistance, cardiovascular disease, and hyperlipidemia. Adipocyte hypertrophy, accelerated adipocyte differentiation, macrophage infiltration, insulin resistance, and the release of inflammatory adipokines and free fatty acids are induced by obesity in adipose tissue. The production of PAI‐1 by adipose tissue is enhanced in obesity because of an increase in fat mass and activation of the proinflammatory state of adipokines in the microenvironment of adipose tissue. Elevated circulating PAI levels are due to an enhancement of PAI‐1 production from adipocytes, macrophages, and vascular endothelial cells in adipose tissue as well as the release of PAI‐1 from the liver.
Figure 9. Figure 9. Role of PAI‐1 and TNF‐α in obesity‐induced glucose/lipid metabolism abnormalities and osteopenia. PAI‐1 deficiency improved insulin resistance and high serum cholesterol levels induced by obesity in female mice, although it did not affect trabecular bone loss and impaired osteoblast differentiation induced by obesity. Obesity induces insulin resistance and hyperlipidemia through PAI‐1, although obesity‐related trabecular bone loss was independent of PAI‐1. On the other hand, TNF‐α seemed to be related to obesity‐induced osteopenia in mice independently of PAI‐1. Data, with permission, from Tamura et al., Ref. .
Figure 10. Figure 10. Role of PAI‐1 in glucocorticoid‐induced diabetes, osteoporosis, and muscle wasting. Glucocorticoid enhances PAI‐1 expression in adipose tissue, contributing to an increase in circulating PAI‐1 levels. This elevation in circulating PAI‐1 induces insulin resistance in the liver, osteoporosis, and muscle wasting in mice. Adipose tissue‐derived PAI‐1 may be important in the pathogenesis of the major adverse effects of glucocorticoid treatment. Data, with permission, from Tamura et al., Ref. .
Figure 11. Figure 11. Mechanism of PAI‐1 actions on bone. PAI‐1 suppresses the levels of osteoblast differentiation markers such as Runx2, Osterix, and alkaline phosphatase in female, but not male murine osteoblasts. Moreover, PAI‐1 deficiency blunts osteoblast differentiation suppressed by diabetes and adipogenic differentiation promoted by diabetes in bone tissue from female, but not male mice. On the other hand, PAI‐1 induced the apoptosis of osteoblasts, although it did not affect the proliferation of osteoblasts in both male and female mice. Data, with permission, from Tamura et al., Ref .


Figure 1. Fibrinolytic system. Plasminogen is converted into plasmin by tPA and uPA. Plasmin resolves the formed fibrin clots by fibrinolysis. PAI‐1 is the most important inhibitor of tPA and uPA. PAI‐1 activation suppresses fibrinolysis, resulting in enhanced fibrinogenesis. FDP, fibrin degradation products.


Figure 2. Fibrinolysis‐independent effects of PAI‐1PAI‐1 interacts with cell surface receptors, vitronectin, uPA/uPAR complexes, and LRP 1. Cells localize both uPA and PAI‐1 leading to the modulation of interrelated events involving extracellular matrix proteins and cell functions, such as migration, proliferation, differentiation, and apoptosis. In this reaction, uPA interacts with cell surface uPAR, and PAI‐1 binds to uPA/uPAR or vitronectin. Subsequent tissue proteolysis modulates extracellular matrix architecture and influences cell‐matrix interactions through integrin receptors and the release of bioactive factors and growth factors affecting cellular functions. LRP1 ligand binding and its complex formation with integrins, growth factor receptors, and proteoglycans induces various protein kinases. Data, with permission, from Czekay et al., Ref. .


Figure 3. Human PAI‐1 promoter and transcription factor binding sites. AP‐1, Activator protein 1‐like binding element; E, E‐box; FKHR, FoxO/forkhead like binding element; HRE, hypoxia response element; NBRE, NGF1‐β responsive element/Nurr77 response element; SP1, stimulatory protein‐1 response element; SRE, Smad3/4‐binding element/TGF‐β response element; VLDL‐RE, very‐low‐density lipoprotein response element. Data, with permission, from Dimova et al., Ref. .


Figure 4. Role of adipose tissue‐derived PAI‐1 in various diseases. Adipose tissue includes adipocytes, macrophages, and vessels. These cells participate in the production of adipokines. The accumulation of fat in adipose tissue and adipokines secreted from adipose tissue are associated with various diseases. PAI‐1 is a crucial adipokine that negatively affects physiological cellular events through mechanisms dependent on and independent of fibrinolysis. The elevations in PAI‐1, TNF‐α, IL‐1, IL‐6, MCP‐1, leptin, and free fatty acids released from adipose tissue as well as a decrease in adiponectin are related to insulin resistance, cardiovascular disease, osteoporosis, sarcopenia, senescence, and cancer. Obesity, inflammation, hypoxia, stress, and corticosteroids induce the dysregulation of adipokine secretion from adipose tissue as well as adipocyte hypertrophy. MCP‐1, monocyte chemoattractant protein‐1.


Figure 5. Role of adipose‐derived MCP‐1 in stress response to diabetes. The diabetes‐induced stress response is composed of two pathways via the sympathetic nervous system leading to the secretion of catecholamines and the hypothalamic‐pituitary‐adrenal axis leading to an increase in glucocorticoids. Macrophage accumulation in adipose tissue is related to the secretion of inflammatory adipokines and the release of free fatty acids related to lipolysis. This pathological modulation promotes the imbalance of glucose metabolism and the coagulation system. Acute stress induces a thrombotic tendency with increases in PAI‐1 levels derived from adipose tissues. Stress induces the production of MCP‐1 from adipose stromal cells, then enhances adipose inflammation and the secretion of proinflammatory adipokines, such as PAI‐1. These adipokines lead to procoagulatory state and insulin resistance, TNF‐α and IL‐6 enhance the production of MCP‐1 from adipocytes and endothelial cells in adipose tissue, and monocytes infiltrating into adipose tissue in response to MCP‐1 secrete TNF‐α and IL‐6. Thus, adipose tissue‐derived MCP‐1 enhances the amplification cascade during chronic inflammation in adipose tissue through autocrine and paracrine interactions among macrophages, adipocytes, and endothelial cells under stress conditions and in the diabetic state. Data, with permission, from Uchida et al., Ref. .


Figure 6. Role of PAI‐1 in diabetic osteoporosis in female mice. The diabetic state enhances the expression of PAI‐1 in the liver, leading to an elevation in circulating PAI‐1 levels in female mice. Then, circulating PAI‐1 suppresses osteoblast differentiation and mineralization, although it enhances adipogenesis in bone marrow tissue, resulting in diabetic osteoporosis. Data, with permission, from Tamura et al., Ref. .


Figure 7. Diabetes, PAI‐1, and adipose‐derived stem cells. Adipose‐derived stem cells are clinically useful for tissue repair and regeneration. Angiogenesis is important for the induction of tissue repair by adipose‐derived stem cells. PAI‐1 levels from adipose‐derived stromal cells are elevated in patients with diabetes, leading to a decrease in angiogenic activity by adipose‐derived stromal cells. Adipose tissue‐derived PAI‐1 might limit the angiogenic activity during tissue repair and regeneration by adipose‐derived stem cells in diabetes. PAI‐1 affects uPA that induces the production of plasmin by the cleavage of plasminogen and the activation of MMPs and growth factors in tissue as well as an activation of urokinase plasminogen activator receptor (uPAR) on the cell surface. This uPA system is important for the migration and invasion of vascular endothelial cells as well as the maintenance of an adequate cell microenvironment during tissue repair. An elevation in circulating and tissue PAI‐1 expression in diabetes may contribute to a decrease in fibrinolytic activity of adipose‐derived stem cells as well as in the cell microenvironment during tissue repair. Data, with permission, from Acosta et al., Ref. ; Dzhoyashvili et al., Ref. ; and Tashiro et al., Ref. . VEGF, vascular endothelial growth factor.


Figure 8. The mechanism by which obesity induces proinflammatory adipokines. Obesity induced by excessive food intake is characterized by the chronic and excessive accumulation of fat and subsequent metabolic disorders with low‐intensity chronic inflammation, resulting in insulin resistance, cardiovascular disease, and hyperlipidemia. Adipocyte hypertrophy, accelerated adipocyte differentiation, macrophage infiltration, insulin resistance, and the release of inflammatory adipokines and free fatty acids are induced by obesity in adipose tissue. The production of PAI‐1 by adipose tissue is enhanced in obesity because of an increase in fat mass and activation of the proinflammatory state of adipokines in the microenvironment of adipose tissue. Elevated circulating PAI levels are due to an enhancement of PAI‐1 production from adipocytes, macrophages, and vascular endothelial cells in adipose tissue as well as the release of PAI‐1 from the liver.


Figure 9. Role of PAI‐1 and TNF‐α in obesity‐induced glucose/lipid metabolism abnormalities and osteopenia. PAI‐1 deficiency improved insulin resistance and high serum cholesterol levels induced by obesity in female mice, although it did not affect trabecular bone loss and impaired osteoblast differentiation induced by obesity. Obesity induces insulin resistance and hyperlipidemia through PAI‐1, although obesity‐related trabecular bone loss was independent of PAI‐1. On the other hand, TNF‐α seemed to be related to obesity‐induced osteopenia in mice independently of PAI‐1. Data, with permission, from Tamura et al., Ref. .


Figure 10. Role of PAI‐1 in glucocorticoid‐induced diabetes, osteoporosis, and muscle wasting. Glucocorticoid enhances PAI‐1 expression in adipose tissue, contributing to an increase in circulating PAI‐1 levels. This elevation in circulating PAI‐1 induces insulin resistance in the liver, osteoporosis, and muscle wasting in mice. Adipose tissue‐derived PAI‐1 may be important in the pathogenesis of the major adverse effects of glucocorticoid treatment. Data, with permission, from Tamura et al., Ref. .


Figure 11. Mechanism of PAI‐1 actions on bone. PAI‐1 suppresses the levels of osteoblast differentiation markers such as Runx2, Osterix, and alkaline phosphatase in female, but not male murine osteoblasts. Moreover, PAI‐1 deficiency blunts osteoblast differentiation suppressed by diabetes and adipogenic differentiation promoted by diabetes in bone tissue from female, but not male mice. On the other hand, PAI‐1 induced the apoptosis of osteoblasts, although it did not affect the proliferation of osteoblasts in both male and female mice. Data, with permission, from Tamura et al., Ref .
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Hiroshi Kaji. Adipose Tissue‐Derived Plasminogen Activator Inhibitor‐1 Function and Regulation. Compr Physiol 2016, 6: 1873-1896. doi: 10.1002/cphy.c160004