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Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH.
Roth, Jonathan D; Veidal, Sanne S; Fensholdt, Louise K D; Rigbolt, Kristoffer T G; Papazyan, Romeo; Nielsen, Jens Christian; Feigh, Michael; Vrang, Niels; Young, Mark; Jelsing, Jacob; Adorini, Luciano; Hansen, Henrik H.
Afiliación
  • Roth JD; Intercept Pharmaceuticals, San Diego, CA, USA.
  • Veidal SS; Gubra, Hørsholm, Denmark.
  • Fensholdt LKD; Gubra, Hørsholm, Denmark.
  • Rigbolt KTG; Gubra, Hørsholm, Denmark.
  • Papazyan R; Intercept Pharmaceuticals, San Diego, CA, USA.
  • Nielsen JC; Gubra, Hørsholm, Denmark.
  • Feigh M; Gubra, Hørsholm, Denmark.
  • Vrang N; Gubra, Hørsholm, Denmark.
  • Young M; Intercept Pharmaceuticals, San Diego, CA, USA.
  • Jelsing J; Gubra, Hørsholm, Denmark.
  • Adorini L; Intercept Pharmaceuticals, San Diego, CA, USA.
  • Hansen HH; Gubra, Hørsholm, Denmark. hbh@gubra.dk.
Sci Rep ; 9(1): 9046, 2019 06 21.
Article en En | MEDLINE | ID: mdl-31227742
Obeticholic acid (OCA) and elafibranor (ELA) are selective and potent agonists for the farnesoid X receptor (FXR) and dual peroxisome proliferator-activated receptor α/δ (PPAR-α/δ), respectively. Both agents have demonstrated clinical efficacy in nonalcoholic steatohepatitis (NASH). The present study used OCA and ELA to compare the effects of mono- and combination therapies on metabolic and histological endpoints in Lepob/ob mice with established diet-induced and biopsy-confirmed NASH (ob/ob-NASH). ob/ob-NASH mice were fed the AMLN diet high in trans-fat, fructose and cholesterol for 15 weeks, whereafter they received vehicle, OCA (30 mg/kg, PO, QD), ELA (3, 10 mg/kg, PO, QD), or combinations (OCA + ELA) for eight weeks. Within-subject comparisons were performed on histomorphometric changes, including fractional area of liver fat, galectin-3 and Col1a1. OCA and ELA monotherapies improved all quantitative histopathological parameters and OCA + ELA combinations exerted additive effects on metabolic and histological endpoints. In agreement with their different molecular mechanisms of action, OCA and ELA monotherapies elicited distinct hepatic gene expression profiles and their combination led to profound transcriptome changes associated with further improvements in lipid handling and insulin signaling, suppression of immune responses and reduced extracellular matrix formation. In conclusion, these findings provide preclinical proof-of-concept for combined FXR and PPAR-α/δ agonist-based therapies in NASH.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Propionatos / Ácido Quenodesoxicólico / Chalconas / Cirrosis Hepática Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Propionatos / Ácido Quenodesoxicólico / Chalconas / Cirrosis Hepática Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Sci Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido