Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha.
Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic Aalpha-, Bbeta-, and gamma-chain mRNA levels to 52% +/- 7%, 46% +/- 8%, and 81% +/- 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% +/- 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the Aalpha-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-alpha (PPARalpha) because a high-affinity ligand for PPARgamma, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPARalpha in the suppression of fibrinogen by fibrates was obtained using PPARalpha-null (-/-) mice. Compared with (+/+) mice, plasma fibrinogen levels in (-/-) mice were significantly higher (3.20 +/- 0.48 v 2.67 +/- 0.42 g/L). Also, hepatic fibrinogen Aalpha-chain mRNA levels were 25% +/- 11% higher in the (-/-) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% +/- 10% of control levels and in hepatic fibrinogen Aalpha-chain mRNA levels to 65% +/- 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPARalpha regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPARalpha.
Kockx
M
M
Gaubius Laboratory, TNO-Prevention and Health, Leiden, The Netherlands; U.325 INSERM, Département d'Athérosclerose, Institut Pasteur, Lille, France.
Gervois
P P
PP
Poulain
P
P
Derudas
B
B
Peters
J M
JM
Gonzalez
F J
FJ
Princen
H M
HM
Kooistra
T
T
Staels
B
B
D000818:Animals; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology*; D058607:Fibric Acids; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020025:Peroxisome Proliferators / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood
D004268:DNA-Binding Proteins; D058607:Fibric Acids; D000960:Hypolipidemic Agents; D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D002995:Clofibric Acid; D005340:Fibrinogen; C006012:fenofibric acid; C019304:ciprofibrate; D002994:Clofibrate; D011345:Fenofibrate