A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice

  • 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.
Author:Pascal HeitelORCiDGND, Giuseppe FaudoneGND, Moritz HelmstädterORCiDGND, Jurema SchmidtGND, Astrid Kaiser, Amelie TjadenORCiD, Martin SchröderORCiDGND, Susanne MüllerORCiD, Simone SchierleGND, Julius PollingerORCiDGND, Daniel MerkORCiDGND
Parent Title (English):Communications chemistry
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:[London]
Document Type:Article
Date of Publication (online):2020/11/13
Date of first Publication:2020/11/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/10/13
Tag:Medicinal chemistry; Pharmacology; Small molecules; Target validation
Issue:art. 174
Article Number:174
Page Number:16
First Page:1
Last Page:16
This research was financially supported by the WIPANO program of the German Federal Ministry for Economic Affairs and Energy (grant 03THW10H09) and by the Aventis Foundation.
Open Access funding enabled and organized by Projekt DEAL.
Institutes:Biochemie, Chemie und Pharmazie
Fachübergreifende Einrichtungen / Buchmann Institut für Molekulare Lebenswissenschaften (BMLS)
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International