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Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury.
Ruart, Maria; Chavarria, Laia; Campreciós, Genís; Suárez-Herrera, Nuria; Montironi, Carla; Guixé-Muntet, Sergi; Bosch, Jaume; Friedman, Scott L; Garcia-Pagán, Juan Carlos; Hernández-Gea, Virginia.
Afiliação
  • Ruart M; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
  • Chavarria L; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
  • Campreciós G; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain.
  • Suárez-Herrera N; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain.
  • Montironi C; Pathology Department, Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, Spain.
  • Guixé-Muntet S; Swiss Liver Centre, Inselspital, Bern University, CH, Switzerland.
  • Bosch J; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain; Swiss Liver Centre, Inselspital, Bern University, CH, S
  • Friedman SL; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States.
  • Garcia-Pagán JC; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain.
  • Hernández-Gea V; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain. Electronic address: vihernandez@clinic.cat.
J Hepatol ; 70(3): 458-469, 2019 03.
Article em En | MEDLINE | ID: mdl-30367898
ABSTRACT
BACKGROUND &

AIMS:

Endothelial dysfunction plays an essential role in liver injury, yet the phenotypic regulation of liver sinusoidal endothelial cells (LSECs) remains unknown. Autophagy is an endogenous protective system whose loss could undermine LSEC integrity and phenotype. The aim of our study was to investigate the role of autophagy in the regulation of endothelial dysfunction and the impact of its manipulation during liver injury.

METHODS:

We analyzed primary isolated LSECs from Atg7control and Atg7endo mice as well as rats after CCl4 induced liver injury. Liver tissue and primary isolated stellate cells were used to analyze liver fibrosis. Autophagy flux, microvascular function, nitric oxide bioavailability, cellular superoxide content and the antioxidant response were evaluated in endothelial cells.

RESULTS:

Autophagy maintains LSEC homeostasis and is rapidly upregulated during capillarization in vitro and in vivo. Pharmacological and genetic downregulation of endothelial autophagy increases oxidative stress in vitro. During liver injury in vivo, the selective loss of endothelial autophagy leads to cellular dysfunction and reduced intrahepatic nitric oxide. The loss of autophagy also impairs LSECs ability to handle oxidative stress and aggravates fibrosis.

CONCLUSIONS:

Autophagy contributes to maintaining endothelial phenotype and protecting LSECs from oxidative stress during early phases of liver disease. Selectively potentiating autophagy in LSECs during early stages of liver disease may be an attractive approach to modify the disease course and prevent fibrosis progression. LAY

SUMMARY:

Liver endothelial cells are the first liver cell type affected after any kind of liver injury. The loss of their unique phenotype during injury amplifies liver damage by orchestrating the response of the liver microenvironment. Autophagy is a mechanism involved in the regulation of this initial response and its manipulation can modify the progression of liver damage.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Falência Hepática Aguda / Células Endoteliais / Fígado / Cirrose Hepática Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Autofagia / Falência Hepática Aguda / Células Endoteliais / Fígado / Cirrose Hepática Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article