Differential regulation of apolipoprotein A-I gene expression by vitamin D receptor modulators.
We have found that 1,25-dihydroxy-cholecalciferol (1,25-(OH)(2)D(3)) 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)(2)D(3) 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)(2)D(3) 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.
Wehmeier
Kent R
KR
Division of Endocrinology, Department of Medicine, University of Florida, 653-1 West 8th Street, 4th Floor LRC, Jacksonville, FL 32209, USA.
Mazza
Angela
A
Hachem
Sahar
S
Ligaray
Ken
K
Mooradian
Arshag D
AD
Wong
Norman C W
NC
Haas
Michael J
MJ
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D018938:Caco-2 Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D018167:Receptors, Calcitriol / Q000187:drug effects*; D030181:Vitamin D Response Element / Q000187:drug effects / Q000235:genetics
D016632:Apolipoprotein A-I; D018167:Receptors, Calcitriol; C470666:ZK 191784; D002117:Calcitriol; C078903:seocalcitol