Fibrates Suppress Fibrinogen Gene Expression in Rodents Via Activation of the Peroxisome Proliferator-Activated Receptor-α

Abstract

AbstractPlasma 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 Aα-, Bβ-, and γ-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 Aα-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-α (PPARα) because a high-affinity ligand for PPARγ, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPARα in the suppression of fibrinogen by fibrates was obtained using PPARα-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 Aα-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 Aα-chain mRNA levels to 65% ± 12% of control levels was seen in (+/+) mice, but not in (−/−) mice. These studies show that PPARα regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPARα.