title: Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis.
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.
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Annelies.paridaens@ugent.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Paridaens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Sarah.Raevens@ugent.be.
authors.forename: Sarah
authors.initials: S
authors.lastname: Raevens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Lindsey.Devisscher@ugent.be.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Eliene.Bogaerts@ugent.be.
authors.forename: Eliene
authors.initials: E
authors.lastname: Bogaerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Xavier.Verhelst@ugent.be.
authors.forename: Xavier
authors.initials: X
authors.lastname: Verhelst
authors.affiliation: Department of Pathology, Ghent University, 9000 Ghent, Belgium. Anne.hoorens@ugent.be.
authors.forename: Anne
authors.initials: A
authors.lastname: Hoorens
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Hans.Vanvlierberghe@ugent.be.
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.affiliation: Liver Cell Biology Lab, Vrije Universiteit Brussel, 1090 Brussels, Belgium. lvgrunsv@vub.ac.be.
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Anja.Geerts@ugent.be.
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.affiliation: Department of Hepatology and Gastroenterology, Ghent University, 9000 Ghent, Belgium. Isabelle.Colle@ugent.be.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001660:Biliary Tract Diseases / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D015153:Blotting, Western; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002779:Cholestasis / Q000150:complications; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D008297:Male; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics
chemical_list: D002756:Cholagogues and Choleretics; C497250:Ddit3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051742:Transcription Factor CHOP; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D053454:Caspase 12; D053148:Caspase 3
keywords: apoptosis; cell death; cirrhosis; endoplasmic reticulum stress; liver fibrosis; tauroursodeoxycholic acid; unfolded protein response