Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on ongoing hepatic fibrosis.

Angiotensin II Type 1 Receptor Blockers / pharmacology Angiotensin Receptor Antagonists / therapeutic use Angiotensin-Converting Enzyme Inhibitors / therapeutic use Animals Humans Liver Cirrhosis / genetics Losartan / pharmacology Matrix Metalloproteinase 2 Non-alcoholic Fatty Liver Disease / drug therapy RNA, Messenger / metabolism Rats Tissue Inhibitor of Metalloproteinase-1 / therapeutic use Toll-Like Receptor 4 Transforming Growth Factor beta1 / metabolism

Angiotensin II receptor blocker Farnesoid X receptor Hepatic regression Hepatic stellate cell Lipopolysaccharide Liver fibrosis Losartan Nonalcoholic steatohepatitis Obeticholic acid TGF beta Toll-like receptor 4

Journal

Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology

ISSN: 0975-0711

Titre abrégé: Indian J Gastroenterol

Pays: India

ID NLM: 8409436

Informations de publication

Date de publication:
04 2022

Historique:

received: 08 04 2021

accepted: 19 09 2021

pubmed: 14 3 2022

medline: 18 5 2022

entrez: 13 3 2022

Statut: ppublish

Résumé

Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model. Fischer 344 rats were fed with choline-deficient L-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated. OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet-induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel. OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis.

Identifiants

DOI: 10.1007/s12664-021-01220-5 PMID: 35279807

pubmed: 35279807

doi: 10.1007/s12664-021-01220-5

pii: 10.1007/s12664-021-01220-5

doi:

Substances chimiques

Angiotensin II Type 1 Receptor Blockers 0

Angiotensin Receptor Antagonists 0

Angiotensin-Converting Enzyme Inhibitors 0

RNA, Messenger 0

Tissue Inhibitor of Metalloproteinase-1 0

Toll-Like Receptor 4 0

Transforming Growth Factor beta1 0

Matrix Metalloproteinase 2 EC 3.4.24.24

Losartan JMS50MPO89

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

169-180

Commentaires et corrections

Type : CommentIn

Informations de copyright

Références

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