TRANSCRIPTIONAL SUPPRESSION OF THE TRANSFERRIN GENE BY HYPOLIPIDEMIC PEROXISOME PROLIFERATORS

Activation of gene expression by hypolipidemic peroxisome proliferator s (e.g. native and substituted long chain fatty acids, aryloxyalkanoic fibrate drugs) is accompanied by transcriptional suppression of liver transferrin gene in treated animals or human hepatoma cell line, Tran scriptional suppression of Liver transferrin by hypolipidemic peroxiso me proliferators results from (a) displacement of hepatic nuclear fact or (HNF)-4 from the transferrin promoter by nonproductive binding of t he peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer to the (-76/-52) PRI promoter element of the human transf errin gene and (b) suppression of liver HNF-4 gene expression by hypol ipidemic peroxisome proliferators with a concomitant decrease in its a vailability for binding to the transferrin PRI promoter element. HNF-4 gene suppression and its displacement from the transferrin promoter r esult in eliminating HNF-4-enhanced transcription of transferrin, Live r transferrin suppression by hypolipidemic peroxisome proliferators ma y result in reduced iron availability as well as modulation of transfe rrin-induced differentiation processes. Transcriptional suppression of HNF-4-enhanced liver genes (e.g. apolipoprotein C-III, transferrin) m ay complement the pleiotropic biological effect exerted by hypolipidem ic peroxisome proliferators.