Differential regulation of apolipoprotein A-I gene expression by vitamin D receptor modulators

Abstract

We have found that 1,25-dihydroxy-cholecalciferol (1,25-(OH)2D3) represses the expression of the apolipoprotein A-I (apo A-I) gene in hepatocytes. In this manuscript we examined the effects of the vitamin D receptor (VDR) modulators EB1089 (EB) and ZK191784 (ZK) on expression of the apo A-I gene in liver (HepG2) and in intestinal (Caco-2) cells. In HepG2 cells, EB and ZK induced apo A-I secretion and gene promoter activity in a dose-dependent manner. This induction did not require the VDR since antisense-mediated inhibition of VDR had no appreciable effect on apo A-I promoter activity in cells treated with EB or ZK. Although repression of apo A-I gene expression by 1,25-(OH)2D3 in hepatocytes required nuclear receptor binding to site A in the promoter, this cis-element was insufficient for induction of apo-AI by EB and ZK. In Caco-2 cells, treatment with 1,25-(OH)2D3 had no effect on apo A-I protein secretion or promoter activity while EB induced and ZK inhibited apo A-I gene expression. Gel shift assays showed that none of the treatments resulted in a change in site A binding activity. These results indicate that VDR modulators in hepatocytes and intestinal cells differentially regulate expression of the apo A-I gene.