Inhibition of plasminogen activator inhibitor type-1 expression in HepG2 cells by fenofibrate may be associated with Smad signaling.

Abstract Background We investigated the molecular mechanism underlying the effect of fenofibrate on expression of plasminogen activator inhibitor type-1 (PAI-1) in HepG2 cells. Methods Luciferase reporter gene plasmids containing four sequentially truncated fragments of the PAI-1 promoter region (− 804 to + 17) were constructed and plasmids carrying constructs of Smad binding element (SBE)-site-directed deletions in the PAI-1 promoter were also generated and then transfected to HepG2 cells prior to fenofibrate treatment. Smad3 and Smad4 protein levels were measured by Western blotting. Results The decreased expression of PAI-1 mRNA and protein was detected in HepG2 cells after exposure to fenofibrate. PAI-1 transcription activities were also down-regulated following exposure to fenofibrate in HepG2 cells when they were transfected with the luciferase reporter gene plasmid containing a full-length of PAI-1 promoter. However, with the truncation of PAI-1 promoter, the inhibitory effect of fenofibrate on the transcription activity of PAI-1 gradually diminished. Furthermore, the transcription activity of PAI-1 was significantly up-regulated by fenofibrate in HepG2 cells when they were transfected with plasmids of the SBEs-deleted PAI-1 promoter. The expression of both Smad3 and Smad4 proteins was suppressed by fenofibrate. Conclusion Fenofibrate exerts its inhibitory effect on PAI-1 transcription in HepG2 cells presumably involving Smad signaling pathways.