Involvement of JNK regulation in oxidative stress-mediated murine liver injury by microcystin-LR.
Microcystin-LR (MC-LR) produced by cyanobacteria in diverse water systems is a potent specific hepatotoxin and has been documented to induce various liver diseases via oxidative stress. However, the underlying mechanisms are largely unknown. In the current study, we investigated the molecular events involved in the oxidative liver injury by MC-LR. Our results demonstrated that MC-LR induced liver injury in mice through a series of steps that began with the production of reactive oxygen species (ROS), which stimulated the sustained activation of JNK and its downstream targets, AP-1 and Bid. Furthermore, the mitochondrial proteomic analysis indicated that JNK activation affected some crucial enzymes of energy metabolism, led to mitochondria dysfunction, which contributed to hepatocyte apoptosis and oxidative liver injury by MC-LR. Our results reveal significant insights into the mechanisms of liver injury induced by microcystins, and serve as a framework for deciphering the role of JNK in oxidative stress-associated liver diseases.
Wei
Yinna
Y
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, People's Republic of China.
Weng
Dan
D
Li
Feng
F
Zou
Xiao
X
Young
D Owen
DO
Ji
Jianguo
J
Shen
Pingping
P
D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008107:Liver Diseases / Q000201:enzymology* / Q000503:physiopathology; D008387:Marine Toxins; D051379:Mice; D052998:Microcystins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; C057862:cyanoginosin LR