Mitogen-activated protein kinase regulates transcription of the ApoCIII gene - Involvement of the orphan nuclear receptor HNF4

The transcriptional regulation of the apoCIII gene by hormonal and metaboli c signals plays a significant role in determining plasma triglyceride level s, In the current work me demonstrate that the apoCIII gene is regulated by the mitogen-activated protein (MAP) kinase signaling pathway, In HepG2 cel ls, repression of MAP kinase activity by treatment with the mitogen-activat ed protein kinase/extracellular signal-regulated kinase kinase inhibitor PD 98059 caused a 5-8-fold increase in apoCIII transcriptional activity, Activ ation of MAP kinase by phorbol ester treatment caused a 3-5-fold reduction in apoCIII transcription. The region of the apoCIII promoter responsible fo r this regulation was mapped in transiently transfected HepG2 cells to a 6- base pair element located at -740, The major protein binding to this site w as identified as the nuclear hormone receptor HNF4, An increase in HNF4 mRN A and protein levels was observed in HepG2 cells after treatment with PD980 59, indicating that the MAP kinase pathway regulates the expression of the HNF4 gene. These findings demonstrate that, the apoCIII gene can be regulat ed by signals acting through the MAP kinase pathway and that this regulatio n is mediated, at least in part, by changes in the amount of HNF4.