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Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells
Fabián Arenas, … , Jesús Prieto, Juan F. Medina
Fabián Arenas, … , Jesús Prieto, Juan F. Medina
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):695-709. https://doi.org/10.1172/JCI33156.
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Research Article Hepatology

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells

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Abstract

Primary biliary cirrhosis (PBC) is a cholestatic disease associated with autoimmune phenomena and alterations in both biliary bicarbonate excretion and expression of the bicarbonate carrier AE2. The bile acid ursodeoxycholic acid (UCDA) is currently used in treatment of cholestatic liver diseases and is the treatment of choice in PBC; however, a subset of PBC patients respond poorly to UDCA monotherapy. In these patients, a combination of UDCA and glucocorticoid therapy appears to be beneficial. To address the mechanism of this benefit, we analyzed the effects of UDCA and dexamethasone on AE2 gene expression in human liver cells from hepatocyte and cholangiocyte lineages. The combination of UDCA and dexamethasone, but not UDCA or dexamethasone alone, increased the expression of liver-enriched alternative mRNA isoforms AE2b1 and AE2b2 and enhanced AE2 activity. Similar effects were obtained after replacing UDCA with UDCA conjugates. In in vitro and in vivo reporter assays, we found that a UDCA/dexamethasone combination upregulated human AE2 alternate overlapping promoter sequences from which AE2b1 and AE2b2 are expressed. In chromatin immunoprecipitation assays, we demonstrated that combination UCDA/dexamethasone treatment induced p300-related interactions between HNF1 and glucocorticoid receptor on the AE2 alternate promoter. Our data provide a potential molecular explanation for the beneficial effects of the combination of UDCA and glucocorticoids in PBC patients with inadequate response to UDCA monotherapy.

Authors

Fabián Arenas, Isabel Hervias, Miriam Úriz, Ruth Joplin, Jesús Prieto, Juan F. Medina

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Figure 1

The combination of UDCA and dexamethasone upregulates AE2 alternative expression in NHCs.

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The combination of UDCA and dexamethasone upregulates AE2 alternative ex...
The mRNA levels for AE2b1, AE2b2, and AE2a isoforms were determined by real-time PCR in cultured NHCs treated for 24 or 72 hours with either dexamethasone (DEX) and/or UDCA, GUDCA, TUDCA, CA, or CDCA (100 μM each) or with just vehicle. Values (normalized for GAPDH mRNA) are given as fold expression relative to values in the respective controls with just vehicle. Data are mean ± SD; n = 6 (except for GUDCA, TUDCA, CA, and CDCA — with and without DEX — for which n = 3 each). *P < 0.05, **P < 0.01, ***P < 0.001 versus vehicle control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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