Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence

Akare, Sandeep; Jean-Louis, Samira; Chen, Wemin; Wood, D.J.; Powell, Ashley A.; Martinez, Jesse D.

doi:10.1002/ijc.22231

Cited by 48 publications

(35 citation statements)

References 68 publications

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“…Here, we showed that DCA in weakly acidic conditions affected the barrier function, indicating that, even if acid suppression is successful, weakly acidic reflux with DCA can damage the esophagus. While bile acids, including GCA, TCA, and DCA, are known to damage barrier function (22,30) or to affect colon tumor promoters (20), UDCA is thought to be chemopreventive (1). Although the solubility of UDCA was low in the culture media, we examined the influence of UDCA at maximum concentration at pH 3, and it did not affect the barrier function.…”

Section: Discussionmentioning

confidence: 99%

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima²,

Tomita³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Experimental models for esophageal epithelium in vitro either suffer from poor differentiation or complicated culture systems. An air-liquid interface system with normal human bronchial epithelial cells can serve as a model of esophageal-like squamous epithelial cell layers. Here, we explore the influence of bile acids on barrier function and tight junction (TJ) proteins. The cells were treated with taurocholic acid (TCA), glycocholic acid (GCA), or deoxycholic acid (DCA) at different pH values, or with pepsin. Barrier function was measured by transepithelial electrical resistance (TEER) and the diffusion of paracellular tracers (permeability). The expression of TJ proteins, including claudin-1 and claudin-4, was examined by Western blotting of 1% Nonidet P-40-soluble and -insoluble fractions. TCA and GCA dose-dependently decreased TEER and increased paracellular permeability at pH 3 after 1 h. TCA (4 mM) or GCA (4 mM) did not change TEER and permeability at pH 7.4 or pH 4. The combination of TCA and GCA at pH 3 significantly decreased TEER and increased permeability at lower concentrations (2 mM). Pepsin (4 mg/ml, pH 3) did not have any effect on barrier function. DCA significantly decreased the TEER and increased permeability at pH 6, a weakly acidic condition. TCA (4 mM) and GCA (4 mM) significantly decreased the insoluble fractions of claudin-1 and claudin-4 at pH 3. In conclusion, acidic bile salts disrupted the squamous epithelial barrier function partly by modulating the amounts of claudin-1 and claudin-4. These results provide new insights for understanding the role of TJ proteins in esophagitis.

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Section: Discussionmentioning

confidence: 99%

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Chen

Oshima²,

Tomita³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…,112 Recent mechanistic studies suggest that, in contrast to butyrate, UDCA induced cell differentiation and senescence in colon cancer cells via histone hypoacetylation. 113 …”

Section: Ursodeoxycholate (Udca)mentioning

confidence: 99%

Diet, the Gut Microbiome, and Epigenetics

Hullar

Fu²

2014

The Cancer Journal

173

116

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Increasingly, the gut microbiome is implicated in the etiology of cancer, not only as an infectious agent, but also by altering exposure to dietary compounds that influence disease risk. While the composition and metabolism of the gut microbiome is influenced by diet, the gut microbiome can also modify dietary exposures in ways that are beneficial or detrimental to the human host. The colonic bacteria metabolize macronutrients, either as specialists or in consortia of bacteria, in a variety of diverse metabolic pathways. Microbial metabolites of diet can also be epigenetic activators of gene expression that may influence cancer risk in humans. Epigenetic involves heritable changes in gene expression via post translational and post transcriptional modifications. Microbial metabolites can influence epigenetics by altering the pool of compounds used for modification or by directly inhibiting enzymes involved in epigenetic pathways. Colonic epithelium is immediately exposed to these metabolites, although some metabolites are also found in systemic circulation. In this review, we discuss the role of the gut microbiome in dietary metabolism and how microbial metabolites may influence gene expression linked to colon cancer risk.

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“…It is currently known that p300, together with its closely related factor CBP, is present in most cell types (46), where it may interact with a large number of DNA-bound nuclear receptors and nuclear factors to form a large acetyltransferase complex - a useful database for the CBP/p300 interactome is currently available ("CBP & p300 interactome database"; found at http://www.stjude.org/brindle) - and participate in second messenger-regulated gene expression (47)(48)(49)(50). Curiously, high doses of UDCA (500 μM) have recently been reported to diminish histone acetylation in several cell lines from colon cancer (51), but this effect appears unrelated to what we have observed in our study, and a direct effect of UDCA on the CBP/p300 complex and interacting nuclear proteins remains to be elucidated. Although the detailed mechanism of action of p300 for AE2 alternate promoter deserves deeper studies, our present data from ChIP assays against p300 in nuclear extracts from nontransfected PLC/PRF/5 cells suggest that this coregulator may interact with DNA-bound HNF1α on the AE2 alternate promoter regardless of any treatment ( Figure 12, B and C).…”

Section: Figure 10mentioning

confidence: 99%

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

Arenas¹,

Hervías²,

Úriz³

et al. 2008

J. Clin. Invest.

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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.

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Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence

Cited by 48 publications

References 68 publications

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Acidic bile salts modulate the squamous epithelial barrier function by modulating tight junction proteins

Diet, the Gut Microbiome, and Epigenetics

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

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