STUDIES ON THE MECHANISM OF FIBRATE-INHIBITED EXPRESSION OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 IN CULTURED-HEPATOCYTES FROM CYNOMOLGUS MONKEY

Fibrates are widely used drugs in hyperlipidemic disorders. In additio n to lowering serum triglyceride levels, fibrates have also been shown to reduce elevated plasma plasminogen activator inhibitor-1 (PAI-1) l evels in vivo. We demonstrate that fibrates suppress PAI-1 synthesis i n cultured cynomolgus monkey hepatocytes in a concentration-dependent way (0.1 to 1.0 mmol/L) and independent of their lipid-lowering effect . Different fibrates showed different potency in suppressing PAI-1 pro duction: gemfibrozil and clofibric acid, at a concentration of 1 mmol/ L, reduced PAI-1 synthesis over 24 hours to 52 +/- 20% and 60 +/- 5%. while clofibrate and bezafibrate lowered PAI-1 synthesis to only 86 +/ - 17% and 84 +/- 15% of control values, respectively. These changes in PAI-1 production by fibrates correlated with changes in PAI-1 mRNA le vels and were also visible at the level of gene transcription. Fibrate s did not lower basal PAI-1 synthesis but attenuated an acceleration o f PAI-1 production during culture. The suppressing effect of fibrates on PAI-1 synthesis could not be mimicked with activators or inhibitors of protein kinase C (PKC). Furthermore, fibrates did not inhibit the increase in PAI-1 synthesis induced by epidermal growth factor or tran sforming growth factor-beta. These results make mechanisms involving P KC modulation or growth factor receptor inactivation as a mode of acti on of fibrates unlikely. The suppressing effect of fibrates on PAI-1 s ynthesis could involve the nuclear receptor peroxisome proliferator-ac tivated receptor (PPAR) and its heterodimeric partner, the retinoid X receptor (RXR). The alpha forms of PPAR and RXR were both found to be expressed in cynomolgus monkey hepatocytes. The ligand for RXR alpha, 9-cis retinoic acid, suppressed PAI-1 synthesis to the same extent as gemfibrozil, while a combination of gemfibrozil and 9-cis retinoic aci d had no more effect on PAI-1 synthesis than any of these compounds al one at optimal concentrations. In conclusion, fibrates downregulate an induced PAI-1 production in cynomolgus monkey hepatocytes independent of a decrease in triglyceride levels. A possible involvement of PPAR alpha/RXR alpha in this down-regulation is discussed.