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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 Article has an altmetric score of 4

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 12

The coregulatory factor p300 may function as a scaffold protein for the interaction of GR and HNF1α on the AE2 alternate promoter in PLC/PRF/5 cells following simultaneous treatment with UDCA and dexamethasone.

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The coregulatory factor p300 may function as a scaffold protein for the ...
(A) ChIP assays with p300 immunoprecipitates from extracts of PLC/PRF/5 cells treated as described in Figure 10, in which the region that includes GREcore –327b1 (amplicon –391b1/–239b1) was amplified. Positive and negative controls were equivalent to those in Figure 10A, but IgG for the negative immunoprecipitation control was mouse total IgG. (B) ChIP assays with p300 immunoprecipitates in which the region that includes the HNF1 element (amplicon –827b1/–534b1) was amplified using the same templates as in A. (C) ChIP assays with p300 immunoprecipitates in which the intervening region between HNF1 and GREcore –327b1 elements (amplicon –571b1/–359b1) was amplified using the same templates as in A. Gray bars in the upper diagrams refer to the corresponding amplicons; gray arrows indicate the HNF1 site; open rhombuses represent GREcore motifs.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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