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Autophagy: A cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress

Bhogal, Ricky H. and Weston, Christopher J. and Curbishley, Stuart M. and Adams, David H. and Afford, Simon C. (2012) Autophagy: A cyto-protective mechanism which prevents primary human hepatocyte apoptosis during oxidative stress. Autophagy, 8 (4). pp. 545-558. ISSN 1554-8627

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URL of Published Version: http://dx.doi.org/10.4161/auto.19012

Identification Number/DOI: doi:10.4161/auto.19012

The role of autophagy in the response of human hepatocytes to oxidative stress remains unknown. Understanding this process may have important implications for the understanding of basic liver epithelial cell biology and the responses of hepatocytes during liver disease. To address this we isolated primary hepatocytes from human liver tissue and exposed them ex vivo to hypoxia and hypoxia-reoxygenation (H-R). We showed that oxidative stress increased hepatocyte autophagy in a reactive oxygen species (ROS) and class III PtdIns3K-dependent manner. Specifically, mitochondrial ROS and NADPH oxidase were found to be key regulators of autophagy. Autophagy involved the upregulation of BECN1, LC3A, Atg7, Atg5 and Atg 12 during hypoxia and H-R. Autophagy was seen to occur within the mitochondria of the hepatocyte and inhibition of autophagy resulted in the lowering a mitochondrial membrane potential and onset of cell death. Autophagic responses were primarily observed in the large peri-venular (PV) hepatocyte subpopulation. Inhibition of autophagy, using 3-methyladenine, increased apoptosis during H-R. Specifically, PV human hepatocytes were more susceptible to apoptosis after inhibition of autophagy. These findings show for the first time that during oxidative stress autophagy serves as a cell survival mechanism for primary human hepatocytes.

Type of Work:Article
Date:2012 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute for Biomedical Research;
Subjects:RC Internal medicine
Institution:University of Birmingham
Copyright Holders:Landes Bioscience
ID Code:1308
Refereed:YES
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