title: Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy.
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.
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Rui
authors: R
authors: Guo
authors: School of Optometry, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, SAR, Hong Kong.
authors: Bin
authors: B
authors: Lin
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Jing Fei
authors: JF
authors: Pan
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Emily C
authors: EC
authors: Liong
authors: Brain Hormone Healthy Aging Centre, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.|Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Ai Min
authors: AM
authors: Xu
authors: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors: Moussa
authors: M
authors: Youdim
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.|Brain Hormone Healthy Aging Centre, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Man Lung
authors: ML
authors: Fung
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.|Brain Hormone Healthy Aging Centre, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: Kwok Fai
authors: KF
authors: So
authors: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.|Brain Hormone Healthy Aging Centre, LKS Faculty of Medicine, The University of Hong Kong, SAR, Hong Kong.
authors: George L
authors: GL
authors: Tipoe
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002251:Carbon Tetrachloride; D053453:Caspase 9 / Q000235:genetics* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009842:Oligopeptides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C403754:benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone; D013912:Threonine; D002251:Carbon Tetrachloride; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C506434:Casp9 protein, mouse; D053453:Caspase 9