Farnesoid X receptor agonist treatment alters bile acid metabolism but exacerbates liver damage in a piglet model of short-bowel syndrome

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dc.contributor.author Pereira-Fantini, Prue M.
dc.contributor.author Lapthorne, Susan
dc.contributor.author Gahan, Cormac G.
dc.contributor.author Joyce, Susan A.
dc.contributor.author Charles, Jenny
dc.contributor.author Fuller, Peter J.
dc.contributor.author Bines, Julie E.
dc.date.accessioned 2017-05-12T10:48:33Z
dc.date.available 2017-05-12T10:48:33Z
dc.date.issued 2017-05-10
dc.identifier.citation Pereira-Fantini, P. M., Lapthorne, S., Gahan, C. G. M., Joyce, S. A., Charles, J., Fuller, P. J. and Bines, J. E. (2017) 'Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome', Cellular and Molecular Gastroenterology and Hepatology, 4(1), pp. 65-74. doi:10.1016/j.jcmgh.2017.02.008 en
dc.identifier.volume 4 en
dc.identifier.issued 1 en
dc.identifier.startpage 65 en
dc.identifier.endpage 74 en
dc.identifier.issn 2352-345X
dc.identifier.uri http://hdl.handle.net/10468/3953
dc.identifier.doi 10.1016/j.jcmgh.2017.02.008
dc.description.abstract Background & Aims: Options for the prevention of short-bowel syndrome–associated liver disease (SBS-ALDs) are limited and often ineffective. The farnesoid X receptor (FXR) is a newly emerging pharmaceutical target and FXR agonists have been shown to ameliorate cholestasis and metabolic disorders. The aim of this study was to assess the efficacy of obeticholic acid (OCA) treatment in preventing SBS-ALDs. Methods: Piglets underwent 75% small-bowel resection (SBS) or sham surgery (sham) and were assigned to either a daily dose of OCA (2.4 mg/kg/day) or were untreated. Clinical measures included weight gain and stool studies. Histologic features were assessed. Ultraperformance liquid chromatography tandem mass spectrometry was used to determine bile acid composition in end point bile and portal serum samples. Gene expression of key FXR targets was assessed in intestinal and hepatic tissues via quantitative polymerase chain reaction. Results: OCA-treated SBS piglets showed decreased stool fat and altered liver histology when compared with nontreated SBS piglets. OCA prevented SBS-associated taurine depletion, however, further analysis of bile and portal serum samples indicated that OCA did not prevent SBS-associated alterations in bile acid composition. The expression of FXR target genes involved in bile acid transport and synthesis increased within the liver of SBS piglets after OCA administration whereas, paradoxically, intestinal expression of FXR target genes were decreased by OCA administration. Conclusions: Administration of OCA in SBS reduced fat malabsorption and altered bile acid composition, but did not prevent the development of SBS-ALDs. We postulate that extensive small resection impacts the ability of the remnant intestine to respond to FXR activation. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier en
dc.rights © 2017 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Short-bowel syndrome en
dc.subject Liver disease en
dc.subject Obeticholic acid en
dc.subject Bile acids en
dc.subject Farnesoid X receptor en
dc.subject Intestinal failure - associated liver disease en
dc.title Farnesoid X receptor agonist treatment alters bile acid metabolism but exacerbates liver damage in a piglet model of short-bowel syndrome en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Cormac Gahan, Microbiology, University College Cork, Cork, Ireland. +353-21-490-3000 Email: c.gahan@ucc.ie en
dc.internal.availability Full text available en
dc.date.updated 2017-05-12T10:41:02Z
dc.description.version Published Version en
dc.internal.rssid 394743286
dc.description.status Peer reviewed en
dc.identifier.journaltitle Cellular And Molecular Gastroenterology And Hepatology en
dc.internal.copyrightchecked No !!CORA!! en
dc.internal.licenseacceptance Yes en
dc.internal.IRISemailaddress c.gahan@ucc.ie en
dc.internal.IRISemailaddress s.joyce@ucc.ie en


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© 2017 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Except where otherwise noted, this item's license is described as © 2017 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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