Differential stimulation by CCAAT/enhancer-binding protein alpha isoforms of the estrogen-activated promoter of the very-low-density apolipoprotein II gene.

The transcription factors CCAAT/enhancer-binding proteins alpha and beta (C/EBP alpha and C/EBP beta) are highly expressed in liver and are believed to function in maintaining the differentiated state of the hepatocytes. C/EBP alpha appears to be a critical regulator of genes involved in metabolic processes. We are interested in the roles of C/EBP in the expression of the very-low-density apolipoprotein II (apoVLDL II) gene. This gene encodes an avian yolk protein, is induced by estrogens and is only expressed in liver. To examine the role of C/EBP in apoVLDL II expression, footprinting and electromobility-shift analysis were performed. For three of the protein-binding sites in the apoVLDL II promoter region, C/EBP alpha and C/EBP beta were identified as the major DNA-binding activities. For one of the C/EBP genes, C/EBP alpha, the effect of the gene products on apoVLDL II transcription was examined. From transfection experiments we conclude that maximal estrogen-dependent activity of the apoVLDL II promoter requires the dual action of the estrogen receptor and C/EBP. The level of activity is different depending on the nature of the C/EBP alpha translational isoform transfected, the full-length C/EBP alpha polypeptide being the most active isoform and the N-terminally truncated isoform being moderately active. The present results suggest a role of C/EBP alpha translational isoform ratio in the modulation of expression of C/EBP target genes, such as those involved in metabolic processes.