scholarly journals Obesity and Breast Cancer: The Roles of Peroxisome Proliferator-Activated Receptor-γand Plasminogen Activator Inhibitor-1

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-13 ◽  
Author(s):  
Jennifer C. Carter ◽  
Frank C. Church
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Activator Inhibitor ◽  
Pai 1

Breast cancer is the most prominent cancer among females in the United States. There are a number of risk factors associated with development of breast cancer, including consumption of a high-fat diet and obesity. Plasminogen activator inhibitor-1 (PAI-1) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer. As a key mediator of adipogenesis and regulator of adipokine production, peroxisome proliferator-activated receptor-γ(PPAR-γ) is involved in PAI-1 expression from adipose tissue. We summarize the current knowledge linking PPAR-γand PAI-1 expression to high-fat diet and obesity in the risk of breast cancer.

Abstract 179: Targeted Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Weight Gain and Prevents Vascular Dysfunction Following a High Fat Diet

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sadiya S Khan ◽  
Alexander Mackie ◽  
Lauren Beussink-Nelson ◽  
Christine E Kamide ◽  
Anne S Henkel ◽  
...  
Keyword(s):  
Weight Gain ◽  
Energy Expenditure ◽  
Plasminogen Activator ◽  
High Fat Diet ◽  
Vascular Dysfunction ◽  
Plasminogen Activator Inhibitor ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Introduction: Elevated plasminogen activator inhibitor-1 (PAI-1) is associated with obesity, but there is controversy whether PAI-1 causes or is a consequence of obesity. We sought to determine whether targeted PAI-1 inhibition with a novel small molecule antagonist (TM5441) alters the development of obesity and/or obesity-induced vascular dysfunction in a diet-induced obesity model. Methods and Results: C57BL/6J mice were fed control, high fat diet (HFD), or high fat diet with TM5441 (HFD+TM5441) for 12 weeks. The HFD had marked weight gain (77±5%) as compared with control (32±2%). TM5441 significantly attenuated weight gain (49±8%, p=0.0075, Figure). HFD-induced hepatic triglyceride accumulation was attenuated by TM5441 (116±31 vs. 76±35 mg trig/g liver, p=0.03). Energy expenditure was reduced in the HFD compared to control (11.1±0.4 vs. 12.9±0.4 kcal/h/kg, p=0.005). However, HFD+TM5441 maintained a level of energy expenditure that was similar to control (13.2±0.6 kcal/h/kg, p=NS). The HFD group demonstrated higher systolic and diastolic blood pressure (141±3; 112±3 mm Hg) compared with control (122±7, 94±8; P<0.05 for both), while administration of TM5441 prevented diet-associated increase (120±6; 93±7 mm Hg, p=NS compared to control) at week 12. Pressure myography of mesenteric arteries in the HFD showed a significant rightward shift in the constrictor response to phenylephrine as compared to control (EC50: 14.5uM vs. 25.1uM, p=0.002). The HFD+TM5441 was similar to control (p=NS). Conclusions: Inhibition of PAI-1 with TM5441 attenuates weight gain, enhances energy expenditure, and prevents obesity-related vascular dysfunction in a murine model of obesity.

Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice

2005 ◽  
Vol 93 (05) ◽  
pp. 816-819 ◽  
Author(s):  
Roger Lijnen
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator. Recent studies in murine models have yielded apparently conflicting data on a potential role of PAI-1 in adipose tissue development and obesity. To reinvestigate this issue, we have rederived PAI-1 deficient (PAI-1-/-) and wild-type (WT) mice and generated true littermates in a 81.25% C57Bl/6: 18.75% 129 SV genetic background. Male 5-week-old PAI-1-/- and WT mice were kept on a high fat diet (20.1 kJ/g) for 15 weeks. Body weight gain was comparable for both genotypes, and at the time of sacrifice total body weights (39 ± 1.1 versus 41 ± 1.2 g) as well as the weights of subcutaneous (SC, 1,520 ± 110 versus 1,480 ± 110 mg) adipose tissue were not significantly different. In contrast, the gonadal (GON, 1,900 ± 43 versus 1,510 ± 86 mg, p < 0.005) tissue mass was larger in PAI-1-/- mice. Plasma levels of insulin, leptin, glucose, triglycerides, total, HDL and LDL cholesterol were comparable for both genotypes. Immunohisto-chemical analysis of SC and GON adipose tissues did not reveal differences in adipocyte size or number between both genotypes, whereas blood vessel density was also comparable for GON fat but lower in SC fat of WT mice. Thus, this study in littermate mice on high fat diet did not reveal an effect of PAI-1 deficiency on body weight, and a differential effect on SC and GON adipose tissue.

Fibrate-modulated Expression of Fibrinogen, Plasminogen Activator Inhibitor-1 and Apolipoprotein A-I in Cultured Cynomolgus Monkey Hepatocytes

1998 ◽  
Vol 80 (12) ◽  
pp. 942-948 ◽  
Author(s):  
M. Kockx ◽  
H. M. G. Princen ◽  
T. Kooistra
Keyword(s):  
Plasminogen Activator ◽  
Cynomolgus Monkey ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Peroxisome Proliferator ◽  
Plasminogen Activator Inhibitor 1 ◽  
Apolipoprotein A ◽  
Activator Inhibitor ◽  
Pai 1

SummaryFibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes.We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα trans-activation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p <0.01) between PPARα transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARα transactivation activity (r = 0.47; p = 0.24), whereas such a correlation was absent for PAI-1 (r = 0.03; p = 0.95). These results strongly suggest an involvement of PPARα in the regulation of fibrinogen gene expression.

scholarly journals Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1

2008 ◽  
Vol 283 (20) ◽  
pp. 13538-13548 ◽  
Author(s):  
Charmi Shah ◽  
Guang Yang ◽  
Ian Lee ◽  
Jacek Bielawski ◽  
Yusuf A. Hannun ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor

scholarly journals Plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G promoter polymorphism is not associated with breast cancer.

2000 ◽  
Vol 47 (1) ◽  
pp. 191-199 ◽  
Author(s):  
J Błasiak ◽  
B Smolarz
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Pcr Amplification ◽  
Plasminogen Activator Inhibitor ◽  
Cancer Tissue ◽  
Plasminogen Activator Inhibitor 1 ◽  
Node Negative ◽  
Node Positive ◽  
Activator Inhibitor ◽  
Pai 1

The antigen content of plasminogen activator inhibitor-1 (PAI-1) in primary breast cancer tissue extracts may be of strong prognostic value: high levels of PAI-1 in tumors predict poor prognosis for patients. The gene encoding PAI-1 is highly polymorphic and an insertion (5G)/deletion (4G) polymorphism in the PAI-1 gene promoter (the 4G/5G polymorphism), may have functional significance in PAI-1 expression. In the present work the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism in subjects with breast cancer were investigated. Tumor tissues were obtained from 100 postmenopausal women with node-negative and node-positive ductal breast carcinoma with uniform tumor size. Blood samples from age matched healthy women served as control. The 4G/5G polymorphism was determined by PCR amplification using the allele specific primers. The distribution of the genotypes of the 4G/5G polymorphism in both control and patients did not differ significantly (P > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no differences in the genotype distributions and allele frequencies between node-positive and node-negative patients. The 4G/5G polymorphism may not be linked with elevated level of PAI-1 observed in breast cancer and therefore may not be associated with appearance and/or progression of breast cancer.

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