Abstract
Activation of gene expression by hypolipidemic peroxisome proliferators (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. Transcriptional suppression of liver transferrin by hypolipidemic peroxisome proliferators results from (a) displacement of hepatic nuclear factor (HNF)-4 from the transferrin promoter by nonproductive binding of the peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer to the (-76/-52) PRI promoter element of the human transferrin gene and (b) suppression of liver HNF-4 gene expression by hypolipidemic peroxisome proliferators with a concomitant decrease in its availability for binding to the transferrin PRI promoter element. HNF-4 gene suppression and its displacement from the transferrin promoter result in eliminating HNF-4-enhanced transcription of transferrin. Liver transferrin suppression by hypolipidemic peroxisome proliferators may result in reduced iron availability as well as modulation of transferrin-induced differentiation processes. Transcriptional suppression of HNF-4-enhanced liver genes (e.g. apolipoprotein C-III, transferrin) may complement the pleiotropic biological effect exerted by hypolipidemic peroxisome proliferators.
Highlights
Transferrin (Tf)1 is highly expressed in the adult mammalian liver and is secreted by hepatocytes into the serum where it functions as an iron transport protein and growth factor for a variety of cells
Since some hypolipidemic drugs/peroxisome proliferators (HD/PPs) are extensively used in humans as hypolipidemic drugs [15] and since transcriptional suppression, rather than activation, mediated by the HD/PP-peroxisome proliferators-activated receptors (PPARs)/RXRPPRE transduction pathway may complement the pleiotropic biological effect exerted by HD/PPs, we became interested in elucidating the mode of action of HD/PPs as putative suppressors of liver Tf
Tf Transcriptional Suppression Is Mediated by PPAR/retinoic acid X receptor (RXR) Binding to the Tf Proximal Promoter—Transfection experiments in hepatoma cells using 5Ј- and 3Ј-deleted mutants of the human Tf gene promoter have previously implicated the first
Summary
Transferrin; CAT, chloramphenicol acetyltransferase; HD/PP, hypolipidemic drug(s)/peroxisome proliferator; HNF-4, hepatic nuclear factor-4; PPAR, peroxisome proliferatoractivated receptor; PPRE, PPAR-activated response element; RXR, retinoic acid X receptor; TK, thymidine kinase. HD/PPs have previously been reported to activate the expression of a variety of discrete genes (e.g. peroxisomal -oxidation genes [6], -oxidation P450IV genes [7], liver genes coding for thyroid hormone-dependent activities [8], and others) as a result of transcriptional activation mediated by binding of peroxisome proliferators-activated receptors (PPARs) to sequence-specific PPAR-activated response elements (PPREs) in the respective promoters (9 –13).. Liver Tf gene suppression by HD/PPs will be shown here to be mediated by PPAR/RXR and to involve the HNF-4 enhancer element of the Tf gene promoter
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