Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis
- Autores
- Basiglio, Cecilia Lorena; Toledo, Flavia Daniela; Boaglio, Andrea Carolina; Arriaga, Sandra Mónica María; Ochoa, Justina Elena; Sanchez Pozzi, Enrique Juan; Mottino, Aldo Domingo; Roma, Marcelo Gabriel
- Año de publicación
- 2014
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Bilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2) . Here, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 μM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditions
Fil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; Argentina
Fil: Toledo, Flavia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Arriaga, Sandra Mónica María. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; Argentina
Fil: Ochoa, Justina Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina - Materia
-
Unconjugated Bilirubin
Oxidative Stress
Hepatocellular Cholestasis
Canalicular Transporters - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/29811
Ver los metadatos del registro completo
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Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasisBasiglio, Cecilia LorenaToledo, Flavia DanielaBoaglio, Andrea CarolinaArriaga, Sandra Mónica MaríaOchoa, Justina ElenaSanchez Pozzi, Enrique JuanMottino, Aldo DomingoRoma, Marcelo GabrielUnconjugated BilirubinOxidative StressHepatocellular CholestasisCanalicular Transportershttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Bilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2) . Here, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 μM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditionsFil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; ArgentinaFil: Toledo, Flavia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Arriaga, Sandra Mónica María. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; ArgentinaFil: Ochoa, Justina Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaSpringer2014-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/29811Basiglio, Cecilia Lorena; Toledo, Flavia Daniela; Boaglio, Andrea Carolina; Arriaga, Sandra Mónica María; Ochoa, Justina Elena; et al.; Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis; Springer; Archives of Toxicology; 88; 2; 11-2014; 501-5140340-5761CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1007/s00204-013-1143-0info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007%2Fs00204-013-1143-0info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:06:23Zoai:ri.conicet.gov.ar:11336/29811instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:06:23.641CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| title |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| spellingShingle |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis Basiglio, Cecilia Lorena Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters |
| title_short |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| title_full |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| title_fullStr |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| title_full_unstemmed |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| title_sort |
Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis |
| dc.creator.none.fl_str_mv |
Basiglio, Cecilia Lorena Toledo, Flavia Daniela Boaglio, Andrea Carolina Arriaga, Sandra Mónica María Ochoa, Justina Elena Sanchez Pozzi, Enrique Juan Mottino, Aldo Domingo Roma, Marcelo Gabriel |
| author |
Basiglio, Cecilia Lorena |
| author_facet |
Basiglio, Cecilia Lorena Toledo, Flavia Daniela Boaglio, Andrea Carolina Arriaga, Sandra Mónica María Ochoa, Justina Elena Sanchez Pozzi, Enrique Juan Mottino, Aldo Domingo Roma, Marcelo Gabriel |
| author_role |
author |
| author2 |
Toledo, Flavia Daniela Boaglio, Andrea Carolina Arriaga, Sandra Mónica María Ochoa, Justina Elena Sanchez Pozzi, Enrique Juan Mottino, Aldo Domingo Roma, Marcelo Gabriel |
| author2_role |
author author author author author author author |
| dc.subject.none.fl_str_mv |
Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters |
| topic |
Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
Bilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2) . Here, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 μM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditions Fil: Basiglio, Cecilia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; Argentina Fil: Toledo, Flavia Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Boaglio, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Arriaga, Sandra Mónica María. Universidad Nacional de Rosario. Facultad de Cs.bioquímicas y Farmaceuticas. Departamento de Bioquímica Clinica; Argentina Fil: Ochoa, Justina Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Sanchez Pozzi, Enrique Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Mottino, Aldo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina |
| description |
Bilirubin is an endogenous antioxidant with cytoprotective properties, and several studies highlight its potential in the treatment of pro-oxidant diseases. We demonstrated that oxidative stress (OS), a key feature in most hepatopathies, induces cholestasis by actin cytoskeleton disarrangement and further endocytic internalization of key canalicular transporters, such as the bile salt export pump (Bsep) and the multidrug resistance-associated protein 2 (Mrp2) . Here, we evaluated the capability of physiological concentrations of unconjugated bilirubin (UB) to limit OS and the impairment in biliary secretory function induced by the model pro-oxidant agent, tert-butylhydroperoxide (tBuOOH). UB fully prevented the formation of reactive oxygen species and membrane lipid peroxidation induced by tBuOOH in isolated rat hepatocytes. In the isolated rat hepatocyte couplet model, UB (17.1 μM) prevented the endocytic internalization of Bsep and Mrp2 and the impairment in their secretory function induced by tBuOOH. UB also prevented actin disarrangement, as evaluated by both plasma membrane bleb formation and actin fluorescent staining. Finally, UB prevented tBuOOH-induced cPKC activation. Experiments in isolated perfused rat livers showed that UB prevents the increase in oxidized glutathione biliary excretion and the drop in bile flow and the biliary excretion of specific Bsep and Mrp2 substrates. We conclude that physiological concentrations of UB are sufficient to prevent the biliary secretory failure induced by OS, by counteracting actin disarrangement and the consequent internalization of canalicular transporters relevant to normal bile formation. This reveals an important role for UB in preserving biliary secretory function under OS conditions |
| publishDate |
2014 |
| dc.date.none.fl_str_mv |
2014-11 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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http://hdl.handle.net/11336/29811 Basiglio, Cecilia Lorena; Toledo, Flavia Daniela; Boaglio, Andrea Carolina; Arriaga, Sandra Mónica María; Ochoa, Justina Elena; et al.; Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis; Springer; Archives of Toxicology; 88; 2; 11-2014; 501-514 0340-5761 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/29811 |
| identifier_str_mv |
Basiglio, Cecilia Lorena; Toledo, Flavia Daniela; Boaglio, Andrea Carolina; Arriaga, Sandra Mónica María; Ochoa, Justina Elena; et al.; Physiological concentrations of unconjugated bilirubin prevent oxidative stress‑induced hepatocanalicular dysfunction and cholestasis; Springer; Archives of Toxicology; 88; 2; 11-2014; 501-514 0340-5761 CONICET Digital CONICET |
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eng |
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eng |
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