Inhibition of LXRα signaling by vitamin D receptor: Possible role of VDR in bile acid synthesis

Jiang, Wei; Miyamoto, Takahide; Kakizawa, Tomoko; Nishio, Shin-ich; Oiwa, Ako; Takeda, Teiji; Hashizume, Kiyoshi

doi:10.1016/j.bbrc.2006.10.027

Cited by 51 publications

(31 citation statements)

References 28 publications

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“…In addition, rat intestinal Cyp3a1 was observed to be up-regulated by 1,25(OH) 2 D 3 treatment both in vivo and in vitro [17][18][19]. Interestingly, VDR activation was able to blunt the liver X receptor (LXRa) signaling in HepG2 cells [27] and could also antagonize the activities of the farnesoid X receptor (FXR) [28], suggesting that cross-talk interactions between these bile acids-related nuclear receptors could lead to changes in transporters and enzymes in the liver. However, these effects are difficult to identify in vivo due to confounding effects and inter-organ interactions.…”

Section: Introductionmentioning

confidence: 87%

Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo

Chow

Sun

Khan

et al. 2009

Biopharm & Drug Disp

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1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)2D3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)2D3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)2D3-treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ostalpha, and Mrp4, and protein levels of PepT1 and Oat1 were decreased in a dose-dependent manner, and the approximately 50% concomitant reduction in FXR, SHP, HNF-1alpha and HNF-4alpha mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)2D3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs.

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Section: Introductionmentioning

confidence: 87%

Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo

Chow

Sun

Khan

et al. 2009

Biopharm & Drug Disp

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“…VDR has been shown to inhibit LXR induction of the rat CYP7A1 gene (Jiang et al, 2006). VDR also interacts with FXR and inhibits the FXR target genes, SHP, bile salt export pump, and ileum bile acid binding protein (Honjo et al, 2006).…”

Section: Han and Chiangmentioning

confidence: 99%

Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7α-Hydroxylase Gene Transcription in Human Hepatocytes

Han

Chiang

2008

Drug Metab Dispos

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ABSTRACT:Lithocholic acid (LCA) is a potent endogenous vitamin D receptor (VDR) ligand. In cholestasis, LCA levels increase in the liver and intestine. The objective of this study is to test the hypothesis that VDR plays a role in inhibiting cholesterol 7␣-hydroxylase (CYP7A1) gene expression and bile acid synthesis in human hepatocytes. Immunoblot analysis has detected VDR proteins in the nucleus of the human hepatoma cell line HepG2 and human primary hepatocytes. 1␣, 25-Dihydroxy-vitamin D 3 or LCA acetate-activated VDR inhibited CYP7A1 mRNA expression and bile acid synthesis, whereas small interfering RNA to VDR completely abrogated VDR inhibition of CYP7A1 mRNA expression in HepG2 cells. Electrophoretic mobility shift assay and mutagenesis analyses have identified the negative VDR response elements that bind VDR/retinoid X receptor ␣ in the human CYP7A1 promoter. Mammalian twohybrid, coimmunoprecipitation, glutathione S-transferase pull-down, and chromatin immunoprecipitation assays show that ligandactivated VDR specifically interacts with hepatocyte nuclear factor 4␣ (HNF4␣) to block HNF4␣ interaction with coactivators or to compete with HNF4␣ for coactivators or to compete for binding to CYP7A1 chromatin, which results in the inhibition of CYP7A1 gene transcription. This study shows that VDR is expressed in human hepatocytes and may play a critical role in the inhibition of bile acid synthesis, thus protecting liver cells during cholestasis.

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“…The prodrug, 1"(OH)D 2 , and the active ligand, 1,25(OH) 2 D 3 , appear to exhibit similar inductive effects on transporters and enzymes in Caco-2 cells in vitro. 11 However, 1,25(OH) 2 D 3 was reported to inhibit the activity of the liver X receptor-alpha (LXR-") in HepG2 VDR-transfected cells 14 and the farnesoid X receptor (FXR) in CV1 VDR-transfected cells, 15 suggesting that there is cross-talk between the nuclear receptors that may further lead to other indirect changes on levels of the transporter and enzyme.…”

Section: Introductionmentioning

confidence: 99%

Comparative Effects of Doxercalciferol (1α-Hydroxyvitamin D2) Versus Calcitriol (1α,25-Dihydroxyvitamin D3) on the Expression of Transporters and Enzymes in the Rat In Vivo

Chow

Sondervan

Jin

et al. 2011

Journal of Pharmaceutical Sciences

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Inhibition of LXRα signaling by vitamin D receptor: Possible role of VDR in bile acid synthesis

Cited by 51 publications

References 28 publications

Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo

Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo

Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7α-Hydroxylase Gene Transcription in Human Hepatocytes

Comparative Effects of Doxercalciferol (1α-Hydroxyvitamin D2) Versus Calcitriol (1α,25-Dihydroxyvitamin D3) on the Expression of Transporters and Enzymes in the Rat In Vivo

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Inhibition of LXRα signaling by vitamin D receptor: Possible role of VDR in bile acid synthesis

Cited by 51 publications

References 28 publications

Effects of 1α,25‐dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivo

Effects of 1α,25‐dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivo

Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7α-Hydroxylase Gene Transcription in Human Hepatocytes

Comparative Effects of Doxercalciferol (1α-Hydroxyvitamin D2) Versus Calcitriol (1α,25-Dihydroxyvitamin D3) on the Expression of Transporters and Enzymes in the Rat In Vivo

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Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo

Effects of 1α,25‐dihydroxyvitamin D₃ on transporters and enzymes of the rat intestine and kidney in vivo