Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome
Identifieur interne : 000557 ( Main/Exploration ); précédent : 000556; suivant : 000558Farnesoid X Receptor Agonist Treatment Alters Bile Acid Metabolism but Exacerbates Liver Damage in a Piglet Model of Short-Bowel Syndrome
Auteurs : Prue M. Pereira-Fantini [Australie] ; Susan Lapthorne [Australie] ; Cormac G. M. Gahan [Irlande (pays)] ; Susan A. Joyce [Irlande (pays)] ; Jenny Charles [Australie] ; Peter J. Fuller [Australie] ; Julie E. Bines [Australie]Source :
- Cellular and Molecular Gastroenterology and Hepatology [ 2352-345X ] ; 2017.
Abstract
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.
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.
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.
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.
Url:
DOI: 10.1016/j.jcmgh.2017.02.008
PubMed: 28560290
PubMed Central: 5439235
Affiliations:
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Pereira-Fantini</name><affiliation wicri:level="1"><nlm:aff id="aff1">Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Lapthorne, Susan" sort="Lapthorne, Susan" uniqKey="Lapthorne S" first="Susan" last="Lapthorne">Susan Lapthorne</name><affiliation wicri:level="1"><nlm:aff id="aff1">Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Gahan, Cormac G M" sort="Gahan, Cormac G M" uniqKey="Gahan C" first="Cormac G. 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Pereira-Fantini</name><affiliation wicri:level="1"><nlm:aff id="aff1">Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Lapthorne, Susan" sort="Lapthorne, Susan" uniqKey="Lapthorne S" first="Susan" last="Lapthorne">Susan Lapthorne</name><affiliation wicri:level="1"><nlm:aff id="aff1">Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Gahan, Cormac G M" sort="Gahan, Cormac G M" uniqKey="Gahan C" first="Cormac G. M." last="Gahan">Cormac G. M. Gahan</name><affiliation wicri:level="1"><nlm:aff id="aff2">APC Microbiome Institute, University College Cork, Cork, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>APC Microbiome Institute, University College Cork, Cork</wicri:regionArea><wicri:noRegion>Cork</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">School of Microbiology, University College Cork, Cork, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>School of Microbiology, University College Cork, Cork</wicri:regionArea><wicri:noRegion>Cork</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">School of Pharmacy, University College Cork, Cork, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>School of Pharmacy, University College Cork, Cork</wicri:regionArea><wicri:noRegion>Cork</wicri:noRegion></affiliation></author><author><name sortKey="Joyce, Susan A" sort="Joyce, Susan A" uniqKey="Joyce S" first="Susan A." last="Joyce">Susan A. Joyce</name><affiliation wicri:level="1"><nlm:aff id="aff2">APC Microbiome Institute, University College Cork, Cork, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>APC Microbiome Institute, University College Cork, Cork</wicri:regionArea><wicri:noRegion>Cork</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5">School of Biochemistry, University College Cork, Cork, Ireland</nlm:aff><country xml:lang="fr">Irlande (pays)</country><wicri:regionArea>School of Biochemistry, University College Cork, Cork</wicri:regionArea><wicri:noRegion>Cork</wicri:noRegion></affiliation></author><author><name sortKey="Charles, Jenny" sort="Charles, Jenny" uniqKey="Charles J" first="Jenny" last="Charles">Jenny Charles</name><affiliation wicri:level="1"><nlm:aff id="aff6">Department of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Veterinary and Agricultural Sciences, University of Melbourne, Parkville</wicri:regionArea><wicri:noRegion>Parkville</wicri:noRegion></affiliation></author><author><name sortKey="Fuller, Peter J" sort="Fuller, Peter J" uniqKey="Fuller P" first="Peter J." last="Fuller">Peter J. Fuller</name><affiliation wicri:level="1"><nlm:aff id="aff8">Hudson Institute of Medical Research, Clayton, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Hudson Institute of Medical Research, Clayton, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation></author><author><name sortKey="Bines, Julie E" sort="Bines, Julie E" uniqKey="Bines J" first="Julie E." last="Bines">Julie E. Bines</name><affiliation wicri:level="1"><nlm:aff id="aff1">Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Intestinal Failure and Clinical Nutrition Group, Murdoch Childrens Research Institute, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff9">Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, Victoria, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, Victoria</wicri:regionArea><wicri:noRegion>Victoria</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Paediatrics, University of Melbourne, Parkville, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, University of Melbourne, Parkville</wicri:regionArea><wicri:noRegion>Parkville</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cellular and Molecular Gastroenterology and Hepatology</title><idno type="eISSN">2352-345X</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background & Aims</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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.</p></sec><sec><title>Conclusions</title><p>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.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Sukhotnik, I" uniqKey="Sukhotnik I">I. Sukhotnik</name></author><author><name sortKey="Siplovich, L" uniqKey="Siplovich L">L. 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Bines</name><name sortKey="Bines, Julie E" sort="Bines, Julie E" uniqKey="Bines J" first="Julie E." last="Bines">Julie E. Bines</name><name sortKey="Charles, Jenny" sort="Charles, Jenny" uniqKey="Charles J" first="Jenny" last="Charles">Jenny Charles</name><name sortKey="Fuller, Peter J" sort="Fuller, Peter J" uniqKey="Fuller P" first="Peter J." last="Fuller">Peter J. Fuller</name><name sortKey="Lapthorne, Susan" sort="Lapthorne, Susan" uniqKey="Lapthorne S" first="Susan" last="Lapthorne">Susan Lapthorne</name></country><country name="Irlande (pays)"><noRegion><name sortKey="Gahan, Cormac G M" sort="Gahan, Cormac G M" uniqKey="Gahan C" first="Cormac G. M." last="Gahan">Cormac G. M. Gahan</name></noRegion><name sortKey="Gahan, Cormac G M" sort="Gahan, Cormac G M" uniqKey="Gahan C" first="Cormac G. M." last="Gahan">Cormac G. M. Gahan</name><name sortKey="Gahan, Cormac G M" sort="Gahan, Cormac G M" uniqKey="Gahan C" first="Cormac G. M." last="Gahan">Cormac G. M. Gahan</name><name sortKey="Joyce, Susan A" sort="Joyce, Susan A" uniqKey="Joyce S" first="Susan A." last="Joyce">Susan A. Joyce</name><name sortKey="Joyce, Susan A" sort="Joyce, Susan A" uniqKey="Joyce S" first="Susan A." last="Joyce">Susan A. Joyce</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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