A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice.
Journal
Communications chemistry
ISSN: 2399-3669
Titre abrégé: Commun Chem
Pays: England
ID NLM: 101725670
Informations de publication
Date de publication:
13 Nov 2020
13 Nov 2020
Historique:
received:
04
05
2020
accepted:
16
10
2020
entrez:
27
1
2023
pubmed:
13
11
2020
medline:
13
11
2020
Statut:
epublish
Résumé
Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.
Identifiants
pubmed: 36703463
doi: 10.1038/s42004-020-00411-z
pii: 10.1038/s42004-020-00411-z
pmc: PMC9814779
doi:
Types de publication
Journal Article
Langues
eng
Pagination
174Subventions
Organisme : Bundesministerium für Wirtschaft und Energie (Federal Ministry for Economic Affairs and Energy)
ID : 03THW10H09
Informations de copyright
© 2020. The Author(s).
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