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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

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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.
Keywords
liver fibrosis, cirrhosis, tauroursodeoxycholic acid, endoplasmic reticulum stress, unfolded protein response, apoptosis, cell death, ENDOPLASMIC-RETICULUM STRESS, REDUCE ER STRESS, RAT HEPATOCYTES, URSODEOXYCHOLIC ACID, CHEMICAL CHAPERONE, IN-VIVO, CHOLESTASIS, INJURY, ACTIVATION, DISEASE

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Citation

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Chicago
Paridaens, Annelies, Sarah Raevens, Lindsey Devisscher, Eliene Bogaerts, Xavier Verhelst, Anne Hoorens, Hans Van Vlierberghe, Leo van Grunsven, Anja Geerts, and Isabelle Colle. 2017. “Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis.” International Journal of Molecular Sciences 18 (1).
APA
Paridaens, Annelies, Raevens, S., Devisscher, L., Bogaerts, E., Verhelst, X., Hoorens, A., Van Vlierberghe, H., et al. (2017). Modulation of the unfolded protein response by tauroursodeoxycholic acid counteracts apoptotic cell death and fibrosis in a mouse model for secondary biliary liver fibrosis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 18(1).
Vancouver
1.
Paridaens A, Raevens S, Devisscher L, Bogaerts E, Verhelst X, Hoorens A, et al. Modulation of the unfolded protein response by tauroursodeoxycholic acid counteracts apoptotic cell death and fibrosis in a mouse model for secondary biliary liver fibrosis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2017;18(1).
MLA
Paridaens, Annelies, Sarah Raevens, Lindsey Devisscher, et al. “Modulation of the Unfolded Protein Response by Tauroursodeoxycholic Acid Counteracts Apoptotic Cell Death and Fibrosis in a Mouse Model for Secondary Biliary Liver Fibrosis.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18.1 (2017): n. pag. Print.
@article{8533716,
  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.},
  articleno    = {214},
  author       = {Paridaens, Annelies and Raevens, Sarah and Devisscher, Lindsey and Bogaerts, Eliene and Verhelst, Xavier and Hoorens, Anne and Van Vlierberghe, Hans and van Grunsven, Leo and Geerts, Anja and Colle, Isabelle},
  issn         = {1422-0067},
  journal      = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
  keyword      = {liver fibrosis,cirrhosis,tauroursodeoxycholic acid,endoplasmic reticulum stress,unfolded protein response,apoptosis,cell death,ENDOPLASMIC-RETICULUM STRESS,REDUCE ER STRESS,RAT HEPATOCYTES,URSODEOXYCHOLIC ACID,CHEMICAL CHAPERONE,IN-VIVO,CHOLESTASIS,INJURY,ACTIVATION,DISEASE},
  language     = {eng},
  number       = {1},
  pages        = {13},
  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},
  url          = {http://dx.doi.org/10.3390/ijms18010214},
  volume       = {18},
  year         = {2017},
}

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