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