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 f or cardiovascular diseases. Among the few compounds known to lower circulat ing fibrinogen levels in humans are certain fibrates. We have studied the r egulation of fibrinogen gene expression by fibrates in rodents. Treatment o f adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days de creased hepatic A alpha-, B beta-, 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 alrea dy 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 exp ression after fenofibrate occurred at the transcriptional level, as exempli fied for the gene for the A alpha-chain. Other fibrates tested showed simil ar effects on fibrinogen expression and transcription. The effect of fibrat es is specific for peroxisome proliferator-activated receptor-alpha (PPAR a lpha) because a high-affinity ligand for PPAR gamma, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinog en expression. Direct evidence for the involvement of PPAR alpha in the sup pression of fibrinogen by fibrates was obtained using PPAR alpha-null (-/-) mice, Compared with (+/+) mice, plasma fibrinogen levels in (-/-) mice wer e significantly higher (3.20 +/- 0.48 v 2.67 +/- 0.42 g/L). Also, hepatic f ibrinogen A alpha-chain mRNA levels were 25% +/- 11% higher in the (-/-) mi ce. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in p lasma fibrinogen to 77% +/- 10% of control levels and in hepatic fibrinogen A alpha-chain mRNA levels to 65% +/- 12% of control levels was seen in (+/ +) mice, but not in (-/-) mice. These studies show that PPAR alpha regulate s basal levels of plasma fibrinogen and establish that fibrate-suppressed e xpression of fibrinogen in rodents is mediated through PPAR alpha. (C) 1999 by The American Society of Hematology.