title: Inhibition of apolipoprotein AI gene expression by 1, 25-dihydroxyvitamin D3.
abstract: Members of the steroid receptor superfamily are known to alter the transcription of apolipoprotein AI (apo AI), the major apoprotein of high-density lipoprotein (HDL). To assess the role of vitamin D receptor (VDR) in apo AI gene expression, we investigated the effect of 1alpha, 25-dihydroxycholecalciferol (1, 25-(OH)2 D3) as well as the vitamin D antagonist ZK-191784 (ZK), on apo AI gene expression and promoter activity in the human hepatoma cell line HepG2. Apo AI secretion and mRNA levels were both suppressed in a dose-dependent manner in HepG2 cells treated 1, 25-(OH)2 D3. This was accompanied by a similar decrease in apo AI promoter activity. Mapping of the vitamin D response element showed that suppression required a region of the apo AI gene promoter identified previously to contain site A. However, vitamin D treatment had no effect on nuclear factor binding to site A of the apo AI promoter. Treatment with vitamin D receptor antagonist ZK inhibited the ability of 1, 25-(OH)2 D3 to repress apo AI promoter activity, while higher doses of ZK increased apo AI promoter activity. ZK did not alter estradiol stimulated apo AI promoter activity. The VDR antisense ODN had no effect on apo AI promoter activity in control cells, however, it reversed the repression normally seen in cells treated with 1, 25-(OH)2D3. It is concluded that 1, 25-(OH)2 D3 suppresses apo A1 gene expression at the transcriptional level, possibly by altering coactivators or corepressors. This effect requires the VDR as well as a vitamin D response element in the apo AI promoter.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Wehmeier
authors.forename: Ann
authors.initials: A
authors.lastname: Beers
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Haas
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zugel
authors.forename: Arshag D
authors.initials: AD
authors.lastname: Mooradian
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D002117:Calcitriol / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases; D006801:Humans; D008113:Liver Neoplasms; D056921:Nuclear Receptor Coactivator 3; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D015513:Oncogene Proteins / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000235:genetics; D047488:Retinoid X Receptors / Q000096:biosynthesis; D015534:Trans-Activators / Q000096:biosynthesis; D030181:Vitamin D Response Element / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D020319:Oligodeoxyribonucleotides, Antisense; D015513:Oncogene Proteins; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D015534:Trans-Activators; C470666:ZK 191784; D004958:Estradiol; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D002117:Calcitriol