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, Jaime; Friedman, Scott L; Garcia-Pagán, Juan Carlos; Hernández-Gea, Virginia (2019). Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. Journal of hepatology, 70(3), pp. 458-469. Elsevier 10.1016/j.jhep.2018.10.015

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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 Atg7 and Atg7 mice as well as rats after CCl 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Guixé Muntet, Sergi and Bosch, Jaime

Subjects:

600 Technology
600 Technology > 610 Medicine & health

ISSN:

0168-8278

Publisher:

Elsevier

Language:

English

Submitter:

Thi Thao Anh Pham

Date Deposited:

17 Dec 2018 09:56

Last Modified:

21 Nov 2019 04:26

Publisher DOI:

10.1016/j.jhep.2018.10.015

PubMed ID:

30367898

Uncontrolled Keywords:

Atg7 Autophagy Endothelial cell Endothelial dysfunction LSEC Liver fibrosis Nitric oxide Nrf2 Oxidative stress eNOS

BORIS DOI:

10.7892/boris.122121

URI:

https://boris.unibe.ch/id/eprint/122121

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