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Potential of Intestine-Selective FXR Modulation for Treatment of Metabolic Disease.
van Zutphen, Tim; Bertolini, Anna; de Vries, Hilde D; Bloks, Vincent W; de Boer, Jan Freark; Jonker, Johan W; Kuipers, Folkert.
Afiliación
  • van Zutphen T; Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands.
  • Bertolini A; University of Groningen, Leeuwarden, The Netherlands.
  • de Vries HD; Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands.
  • Bloks VW; Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands.
  • de Boer JF; University of Groningen, Leeuwarden, The Netherlands.
  • Jonker JW; Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands.
  • Kuipers F; Department of Pediatrics, University Medical Center Groningen, Faculty Campus Fryslân, University of Groningen, Groningen, The Netherlands.
Handb Exp Pharmacol ; 256: 207-234, 2019.
Article en En | MEDLINE | ID: mdl-31236687
Farnesoid X receptor controls bile acid metabolism, both in the liver and intestine. This potent nuclear receptor not only maintains homeostasis of its own ligands, i.e., bile acids, but also regulates glucose and lipid metabolism as well as the immune system. These findings have led to substantial interest for FXR as a therapeutic target and to the recent approval of an FXR agonist for treating primary biliary cholangitis as well as ongoing clinical trials for other liver diseases. Given that FXR biology is complex, including moderate expression in tissues outside of the enterohepatic circulation, temporal expression of isoforms, posttranscriptional modifications, and the existence of several other bile acid-responsive receptors such as TGR5, clinical application of FXR modulators warrants thorough understanding of its actions. Recent findings have demonstrated remarkable physiological effects of targeting FXR specifically in the intestine (iFXR), thereby avoiding systemic release of modulators. These include local effects such as improvement of intestinal barrier function and intestinal cholesterol turnover, as well as systemic effects such as improvements in glucose homeostasis, insulin sensitivity, and nonalcoholic fatty liver disease (NAFLD). Intriguingly, metabolic improvements have been observed with both an iFXR agonist that leads to production of enteric Fgf15 and increased energy expenditure in adipose tissues and antagonists by reducing systemic ceramide levels and hepatic glucose production. Here we review the recent findings on the role of intestinal FXR and its targeting in metabolic disease.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Intestinos / Enfermedades Metabólicas Límite: Humans Idioma: En Revista: Handb Exp Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Países Bajos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptores Citoplasmáticos y Nucleares / Intestinos / Enfermedades Metabólicas Límite: Humans Idioma: En Revista: Handb Exp Pharmacol Año: 2019 Tipo del documento: Article País de afiliación: Países Bajos