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Vitamin D receptor is expressed in human livers and inhibits CYP7A1 gene transcription
Author(s) -
Han Shuxin,
Chiang John Y. L.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.921.8
Subject(s) - calcitriol receptor , chromatin immunoprecipitation , farnesoid x receptor , g protein coupled bile acid receptor , cholesterol 7 alpha hydroxylase , microbiology and biotechnology , nuclear receptor coactivator 1 , lithocholic acid , reporter gene , biology , transcription factor , receptor , chemistry , nuclear receptor , bile acid , endocrinology , gene expression , biochemistry , promoter , gene
Lithocholic acid (LCA) is a potent endogenous ligand of Vitamin D receptor (VDR). It is thought that VDR may induce intestinal CYP3A4 to detoxify bile acids and protective against colon cancer. It has been reported that VDR is expressed in the rat but not mouse liver. The objective of this study is to identify VDR in human hepatocytes and to test our hypothesis that VDR may inhibit transcription of the gene encoding CYP7A1, the rate‐limiting enzyme in bile acid synthesis in hepatocytes. Immunoblot and real‐time PCR analyses have detected VDR protein and mRNA expression in HepG2 and human primary hepatocytes. Confocal immunofluorescence has detected VDR in the cytoplasm of hepatocytes. Upon treatment with 1α, 25(OH) 2 ‐VD 3 or LCA, VDR is redistributed to the nucleus and cell membrane. Reporter assays showed that 1α, 25(OH) 2 VD 3 and LCA‐acetate decreased human CYP7A1 reporter activities. The region conferring VDR inhibition was localized between −80 and −150 of the human CYP7A1 promoter. VDR decreased hepatocyte nuclear factor 4α (HNF4α) interaction with peroxisome proliferators‐activated receptor γ coactivator 1α (PGC‐1α)/glucocorticoid receptor interacting protein‐1 (GRIP‐1) and trans‐activation of CYP7A1. Co‐immunoprecipitation and GST pull down assays showed that VDR interacted with HNFα. Chromatin immunoprecipitation (CHIP) assay revealed that 1, 25(OH) 2 ‐VD 3 ‐activated VDR interacted with HNF4α and blocked its recruitment of PGC‐1α and GRIP‐1 to the human CYP7A1 chromatin, and resulted in inhibition of CYP7A1 gene transcription. This study suggests that VDR may play a role in protecting liver cells against bile acid toxicity and cholestatic liver injury.