Fibrate-modulated expression of fibrinogen, plasminogen activator inhibitor-1 and apolipoprotein A-I in cultured cynomolgus monkey hepatocytes -- role of the peroxisome proliferator-activated receptor-alpha.

Fibrates 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-alpha (PPARalpha), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARalpha/RXRalpha heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARalpha transactivation activity as determined in a PPARalpha-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 PPARalpha transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARalpha 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 PPARalpha in the regulation of fibrinogen gene expression.