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.
Kockx
M
M
Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.
Princen
H M
HM
Kooistra
T
T
D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D000077556:Alitretinoin; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019281:Dimerization; D005260:Female; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D058607:Fibric Acids; D005340:Fibrinogen / Q000096:biosynthesis* / Q000235:genetics; D015248:Gemfibrozil / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017930:Genes, Reporter; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000502:physiology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology
D016632:Apolipoprotein A-I; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D020025:Peroxisome Proliferators; D017395:Plasminogen Activator Inhibitor 1; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015117:5,8,11,14-Eicosatetraynoic Acid; D000077556:Alitretinoin; D002995:Clofibric Acid; D014212:Tretinoin; C006253:pirinixic acid; D005340:Fibrinogen; C006012:fenofibric acid; C019304:ciprofibrate; D002994:Clofibrate; D015248:Gemfibrozil; D011345:Fenofibrate