Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice.
ACLY
GLP-1R agonist
MASH
NAFLD
NASH
bempedoic acid
combination treatment
fatty acid metabolism
hepatic fibrosis
lipogenesis
liraglutide
mouse model
semaglutide
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
19 09 2023
19 09 2023
Historique:
received:
10
03
2023
revised:
17
07
2023
accepted:
21
08
2023
medline:
22
9
2023
pubmed:
21
9
2023
entrez:
20
9
2023
Statut:
ppublish
Résumé
Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.
Identifiants
pubmed: 37729871
pii: S2666-3791(23)00360-9
doi: 10.1016/j.xcrm.2023.101193
pmc: PMC10518624
pii:
doi:
Substances chimiques
Acyltransferases
EC 2.3.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101193Subventions
Organisme : CIHR
ID : 201709FDN-CEBA-116200
Pays : Canada
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests G.R.S. has received research funding from Esperion Therapeutics, Nestle, Cambrian Biosciences, Novo Nordisk, Poxel Pharmaceuticals, and Espervita Therapeutics; honoraria and/or consulting fees from Astra Zeneca, Cambrian Biosciences, Eli-Lilly, Esperion Therapeutics, Fibrocor Therapeutics, Poxel Therapeutics, and Merck; and is a founder and shareholder of Espervita Therapeutics. S.L.P. is an employee and shareholder of Esperion Therapeutics.
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