Low retinol levels differentially modulate bile salt–induced expression of human and mouse hepatic bile salt transporters†

Abstract

The farnesoid X receptor/retinoid X receptor-alpha (FXR/RXR␣) 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, RXR␣ 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/RXR␣-transfected HepG2 cells exposed to chenodeoxycholic acid (CDCA) and/or 9cRA.

Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms

“…Further, atRA and CDCA demonstrated a synergistic effect in their mRNA expression. This synergistic effect on SHP expression and the attenuation of BSEP induction was also reported by others when HepG2 cells were treated with CDCA and 9cRA ( 52,53 ). However, in those studies reduced FXR/RXR binding to the FXRE in the human BSEP promoter was observed in gel-shift and pulldown assays.…”

Human FXR Regulates SHP Expression through Direct Binding to an LRH-1 Binding Site, Independent of an IR-1 and LRH-1

“…Earlier, we and others have shown that these ligands have opposite effects on binding of FXR/RXRα to the IR-1 and the resulting transcriptional activity of the human BSEP promoter [18], [19]. FXR ligands (both CDCA and GW4064) strongly increase FXR/RXRα-mediated expression of BSEP, while co-administration of 9cRA effectively represses this effect.…”

“…9cRA strongly reduced the binding of FXR/RXRα to the IR-1 sequences as they are present in the human BSEP and SHP promoters. In contrast to the effect on BSEP expression, however, CDCA and 9cRA synergistically activate SHP transcription, in both in vivo and in vitro experiments [19]. This suggests that the mechanisms by which these ligands control FXR/RXRα-mediated regulation of BSEP and SHP may be fundamentally different, while they are both considered to be “typical” FXR/RXRα target genes.…”

Bile acid transporters

“…Another potential regulator of BSEP is vitamin A. FXR functions as a heterodimer with RXR, and in vitro studies suggest that 9-cis retinoic acid activation of RXR inhibits the FXR-induced transcription of human BSEP ( 143 ). This observation was recently confi rmed and diet studies in mice showed that the combination of vitamin A-defi ciency and cholic acid feeding resulted in the highest levels of BSEP expression ( 144 ).…”