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Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis

Authors :
Annelies Paridaens
Sarah Raevens
Lindsey Devisscher
Eliene Bogaerts
Xavier Verhelst
Anne Hoorens
Hans Van Vlierberghe
Leo A. van Grunsven
Anja Geerts
Isabelle Colle
Source :
International Journal of Molecular Sciences, Vol 18, Iss 1, p 214 (2017)
Publication Year :
2017
Publisher :
MDPI AG, 2017.

Abstract

The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death.

Details

Language :
English
ISSN :
14220067
Volume :
18
Issue :
1
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.5471860e3a8e41a9a18d5649d8afd85f
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms18010214