11beta-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women.
BACKGROUND
Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients.


OBJECTIVE
We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction.


METHODS
Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated.


RESULTS
Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid.


CONCLUSIONS
Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.
Ayachi
S Ei
SE
INSERM U626, Université de la Méditerranée, Marseilles and Faculté de Médecine, Université de la Méditerranée, Marseilles, France.
Paulmyer-Lacroix
O
O
Verdier
M
M
Alessi
M-C
MC
Dutour
A
A
Grino
M
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000328:Adult; D002318:Cardiovascular Diseases / Q000209:etiology; D003348:Cortisone / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000201:enzymology*; D009765:Obesity / Q000150:complications / Q000201:enzymology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques
D004791:Enzyme Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone