Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary
Background & Aims: Options for the prevention of short-bowel syndromeâassociated 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-07-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X17300413 |
| _version_ | 1818968820276002816 |
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| author | Prue M. Pereira-Fantini Susan Lapthorne Cormac G.M. Gahan Susan A. Joyce Jenny Charles Peter J. Fuller Julie E. Bines |
| author_facet | Prue M. Pereira-Fantini Susan Lapthorne Cormac G.M. Gahan Susan A. Joyce Jenny Charles Peter J. Fuller Julie E. Bines |
| author_sort | Prue M. Pereira-Fantini |
| collection | DOAJ |
| description | Background & Aims: Options for the prevention of short-bowel syndromeâassociated 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. Keywords: Short-Bowel Syndrome, Liver Disease, Intestinal FailureâAssociated Liver Disease, Obeticholic Acid, Bile Acids, Farnesoid X Receptor |
| first_indexed | 2024-12-20T14:10:46Z |
| format | Article |
| id | doaj.art-f1dafa330ede4f819a36297c5e045d8e |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-20T14:10:46Z |
| publishDate | 2017-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-f1dafa330ede4f819a36297c5e045d8e2022-12-21T19:38:09ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2017-07-01416574Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummaryPrue M. Pereira-Fantini0Susan Lapthorne1Cormac G.M. Gahan2Susan A. Joyce3Jenny Charles4Peter J. Fuller5Julie E. Bines6Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, AustraliaIntestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, AustraliaAPC Microbiome Institute, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, IrelandAPC Microbiome Institute, University College Cork, Cork, Ireland; School of Biochemistry, University College Cork, Cork, IrelandDepartment of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, AustraliaHudson Institute of Medical Research, Clayton, Victoria, AustraliaIntestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia; Department of Gastroenterology and Clinical Nutrition, Royal Childrenâs Hospital, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Australia; Correspondence Address correspondence to: Julie E. Bines, MD, FRACP, Department of Paediatrics, The University of Melbourne, Royal Childrenâs Hospital, Level 2, 50 Flemington Road, Parkville, Victoria 3052, Australia. fax: (613) 9345-6667.Background & Aims: Options for the prevention of short-bowel syndromeâassociated 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. Keywords: Short-Bowel Syndrome, Liver Disease, Intestinal FailureâAssociated Liver Disease, Obeticholic Acid, Bile Acids, Farnesoid X Receptorhttp://www.sciencedirect.com/science/article/pii/S2352345X17300413 |
| spellingShingle | Prue M. Pereira-Fantini Susan Lapthorne Cormac G.M. Gahan Susan A. Joyce Jenny Charles Peter J. Fuller Julie E. Bines Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary |
| title_full | Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary |
| title_fullStr | Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary |
| title_full_unstemmed | Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary |
| title_short | Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel SyndromeSummary |
| title_sort | farnesoid x receptor agonist treatment alters bile acid metabolism buta exacerbates liver damage in a piglet model of short bowela syndromesummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X17300413 |
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