Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/62219
Title: Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy
Authors: Guo, R
Lin, B 
Pan, JF
Liong, EC
Xu, AM
Youdim, M
Fung, ML
So, KF
Tipoe, GL
Issue Date: 2016
Source: Scientific reports, 1 2016, v. 6, no. , p. 1-13
Abstract: Acute liver disease is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long term clinical outcome and lead to liver failure or cancer. Here, we initially demonstrated the beneficial role of caspase-9-dependent autophagy in acute liver injury. Treatment with caspase-9 inhibitor z-LEHD-FMK in HepG2 cells, AML12 cells and C57BL/b6N mice exacerbated CCl4 -induced acute hepatocellular damage, and also down-regulated autophagy markers expression levels, indicating that caspase-9 inhibition may aggravate acute liver damage by suppressing cytoprotective autophagy. CCl4 was used as an acute liver injury inducer which caused oxidative stress and apoptosis through up-regulation of HIF-1α, as well as triggered hepatic inflammation and necroptosis via TLR4/NF-κ B pathway. Caspase-9 Thr125 site was firstly phosphorylated by ERK1/2 which subsequently activated the cytoprotective autophagy process to attenuate acute CCl4 injury. Caspase-9 inhibition further aggravated hepatic necroptosis through NF-κ B expression, leading to increased pro-inflammatory mediators levels, suggesting a protective role of caspase-9-dependent autophagy in the inflammatory process as well as its possibility being a new therapeutic target for the treatment of acute liver injury.
Publisher: Nature Publishing Group
Journal: Scientific reports 
EISSN: 2045-2322
DOI: 10.1038/srep32447
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2016
The following publication Guo, R. et al. Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy. Sci. Rep. 6, 32447 (2016) is available at https://dx.doi.org/10.1038/srep32447
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