Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis

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 f...

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Autores principales:	Basiglio, Cecilia Lorena, Toledo, Flavia D., Boaglio, Andrea C., Arriaga, Sandra Mónica María, Ochoa, Justina E., Sánchez Pozzi, Enrique Juan, Mottino, Aldo D., Roma, Marcelo Gabriel
Formato:	article artículo publishedVersion
Lenguaje:	Inglés
Publicado:	Springer 2018
Materias:	Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters
Acceso en línea:	http://hdl.handle.net/2133/10482 http://hdl.handle.net/2133/10482
Aporte de:	Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR) de Universidad Nacional de Rosario

id	I15-R121-2133-10482
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institution	Universidad Nacional de Rosario
institution_str	I-15
repository_str	R-121
collection	Repositorio Hipermedial de la Universidad Nacional de Rosario (UNR)
language	Inglés
topic	Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters
spellingShingle	Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters Basiglio, Cecilia Lorena Toledo, Flavia D. Boaglio, Andrea C. Arriaga, Sandra Mónica María Ochoa, Justina E. Sánchez Pozzi, Enrique Juan Mottino, Aldo D. Roma, Marcelo Gabriel Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis
topic_facet	Unconjugated Bilirubin Oxidative Stress Hepatocellular Cholestasis Canalicular Transporters
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). He re, 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 (ROS) 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.
format	article artículo publishedVersion
author	Basiglio, Cecilia Lorena Toledo, Flavia D. Boaglio, Andrea C. Arriaga, Sandra Mónica María Ochoa, Justina E. Sánchez Pozzi, Enrique Juan Mottino, Aldo D. Roma, Marcelo Gabriel
author_facet	Basiglio, Cecilia Lorena Toledo, Flavia D. Boaglio, Andrea C. Arriaga, Sandra Mónica María Ochoa, Justina E. Sánchez Pozzi, Enrique Juan Mottino, Aldo D. Roma, Marcelo Gabriel
author_sort	Basiglio, Cecilia Lorena
title	Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis
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
publisher	Springer
publishDate	2018
url	http://hdl.handle.net/2133/10482 http://hdl.handle.net/2133/10482
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Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis

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