Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy

Rui Guo; Bin Lin; Jing Fei Pan; Emily C Liong; Ai Min Xu; Moussa Youdim; Man Lung Fung; Kwok Fai So; George L Tipoe

doi:10.1038/srep32447

Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy

Sci Rep. 2016 Sep 1:6:32447. doi: 10.1038/srep32447.

Authors

Rui Guo¹, Bin Lin², Jing Fei Pan¹, Emily C Liong¹, Ai Min Xu^{3

4}, Moussa Youdim⁵, Man Lung Fung^{1

3}, Kwok Fai So^{1

3}, George L Tipoe^{1

3}

Affiliations

¹ School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
² School of Optometry, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, SAR, Hong Kong.
³ Brain Hormone Healthy Aging Centre, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
⁴ Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
⁵ Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

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-κB 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-κB 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / drug effects
Autophagy / genetics*
Carbon Tetrachloride
Caspase 9 / genetics*
Caspase 9 / metabolism
Chemical and Drug Induced Liver Injury / genetics*
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / pathology
Female
Gene Expression Regulation
Hep G2 Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism
NF-kappa B / genetics*
NF-kappa B / metabolism
Oligopeptides / pharmacology
Oxidative Stress
Phosphorylation
Signal Transduction
Threonine / metabolism
Toll-Like Receptor 4 / genetics*
Toll-Like Receptor 4 / metabolism

Substances

Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit
NF-kappa B
Oligopeptides
Tlr4 protein, mouse
Toll-Like Receptor 4
benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone
Threonine
Carbon Tetrachloride
Mapk1 protein, mouse
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Casp9 protein, mouse
Caspase 9