Low retinol levels differentially modulate bile salt-induced expression of human and mouse hepatic bile salt transporters. Hepatology (Baltimore, Md.) [Hepatology] Journal article | | Title | Low retinol levels differentially modulate bile salt-induced expression of human and mouse hepatic bile salt transporters. | | Author(s) | Hoeke MO, Plass JR, Heegsma J, Geuken M, van Rijsbergen D, Baller JF, Kuipers F, Moshage H, Jansen PL, Faber KN | | Institution | Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. | | Source | Hepatology 2009 Jan; 49(1):151-9. | | MeSH | ATP-Binding Cassette Transporters
Animals
Carcinoma, Hepatocellular
Cell Line, Tumor
Chenodeoxycholic Acid
Cholic Acid
DNA-Binding Proteins
Gene Expression Regulation
Humans
Male
Mice
Mice, Inbred C57BL
Organic Anion Transporters, Sodium-Dependent
Receptors, Cytoplasmic and Nuclear
Response Elements
Retinoid X Receptor alpha
Symporters
Transcription Factors
Tretinoin
Vitamin A
Vitamin A Deficiency
| | Abstract | The farnesoid X receptor/retinoid X receptor-alpha (FXR/RXRalpha) complex regulates bile salt homeostasis, in part by modulating transcription of the bile salt export pump (BSEP/ABCB11) and small heterodimer partner (SHP/NR0B2). FXR is activated by bile salts, RXRalpha by the vitamin A derivative 9-cis retinoic acid (9cRA). Cholestasis is associated with vitamin A malabsorption. Therefore, we evaluated the role of vitamin A/9cRA in the expression of human and mouse bile salt export pump (hBSEP/mBsep), small heterodimer partner (hSHP/mShp), and mouse sodium-dependent taurocholate co-transporting polypeptide (mNtcp). HBSEP and hSHP transcription were analyzed in FXR/RXRalpha-transfected HepG2 cells exposed to chenodeoxycholic acid (CDCA) and/or 9cRA. BSEP promoter activity was determined by luciferase reporter assays, DNA-binding of FXR and RXRalpha by pull-down assays. Serum bile salt levels and hepatic expression of Bsep, Shp, and Ntcp were determined in vitamin A-deficient (VAD)/cholic acid (CA)-fed C57BL/6J mice. Results indicated that 9cRA strongly repressed the CDCA-induced BSEP transcription in HepG2 cells, whereas it super-induced SHP transcription; 9cRA reduced DNA-binding of FXR and RXRalpha. The 9cRA repressed the CDCA-induced BSEP promoter activity irrespective of the exact sequence of the FXR-binding site. In vivo, highest Bsep messenger RNA (mRNA), and protein expression was observed in CA-fed VAD mice. Shp transcription was highest in CA-fed vitamin A-sufficient mice. Ntcp protein expression was strongly reduced in CA-fed VAD mice, whereas mRNA levels were normal. CA-fed control and VAD mice had similarly increased serum bile salt levels.
Conclusion: We showed that 9cRA has opposite effects on bile salt-activated transcription of FXR/RXRalpha target genes. Vitamin A deficiency in CA-fed mice leads to high BSEP expression. Clearance of serum bile salts may, however, be limited because of post-transcriptional reduction of Ntcp. The molecular effects of vitamin A supplementation during cholestasis need further analysis to predict a therapeutic effect. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19111018 |
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