Negative Regulation of Human Fibrinogen Gene Expression by Peroxisome Proliferator-activated Receptor α Agonists via Inhibition of CCAAT Box/Enhancer-binding Protein β

Fibrinogen is a coagulation factor and an acute phase reactant up-regulated by inflammatory cytokines, such as interleukin 6 (IL-6). Elevated plasma fibrinogen levels are associated with coronary heart diseases. Fibrates are clinically used hypolipidemic drugs that act via the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). In addition, most fibrates also reduce plasma fibrinogen levels, but the molecular mechanism is unknown. In this study, we demonstrate that fibrates decrease basal and IL-6-stimulated expression of the human fibrinogen-β gene in human primary hepatocytes and hepatoma HepG2 cells. Fibrates diminish basal and IL-6-induced fibrinogen-β promoter activity, and this effect is enhanced in the presence of co-transfected PPARα. Site-directed mutagenesis experiments demonstrate that PPARα activators decrease human fibrinogen-β promoter activity via the CCAAT box/enhancer-binding protein (C/EBP) response element. Co-transfection of the transcriptional intermediary factor glucocorticoid receptor-interacting protein 1/transcriptional intermediary factor 2 (GRIP1/TIF2) enhances fibrinogen-β gene transcription and alleviates the repressive effect of PPARα. Co-immunoprecipitation experiments demonstrate that PPARα and GRIP1/TIF2 physically interact in vivo in human liver. These data demonstrate that PPARα agonists repress human fibrinogen gene expression by interference with the C/EBPβ pathway through titration of the coactivator GRIP1/TIF2. We observed that the anti-inflammatory action of PPARα is not restricted to fibrinogen but also applies to other acute phase genes containing a C/EBP response element; it also occurs under conditions in which the stimulating action of IL-6 is potentiated by dexamethasone. These findings identify a novel molecular mechanism of negative gene regulation by PPARα and reveal the direct implication of PPARα in the modulation of the inflammatory gene response in the liver.