Basic—Liver, Pancreas, and Biliary TractDeletion of Apoptosis Signal-Regulating Kinase 1 Attenuates Acetaminophen-Induced Liver Injury by Inhibiting c-Jun N-Terminal Kinase Activation
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Animals
The generation of ASK1−/−, JNK1−/−, JNK2−/−, and p38α+/– mice has been described previously.22, 23, 24 All mice were back-crossed into the C57BL/6 strain at least 6 times. Male ASK1−/−, JNK1−/−, JNK2−/−, and p38α+/− mice, 8–10 weeks old, and appropriate age-matched male C57BL/6 wild-type mice (WT; Clea Japan, Tokyo, Japan) were used in all experiments.
The study design and protocols were approved by our institutional ethics committee for animal experimentation. All experiments were conducted in
Both JNK and ASK1 Are Involved in APAP-Induced Liver Injury
A single intraperitoneal injection of APAP (300 mg/kg) induced significant liver injury and marked increases in serum alanine aminotransferase (ALT) levels at 6 hours, peaking at 24 hours, in WT mice. To determine the role of ASK1 in APAP-induced liver injury, ASK1−/− and WT mice were given 300 mg/kg APAP and killed at 6 and 24 hours posttreatment. The increase of serum ALT levels at 6 and 24 hours posttreatment were reduced significantly in ASK1−/− mice compared with WT mice (Figure 1A) The
Discussion
Recent studies have reported that ASK1 is involved in the pathogenesis of various human diseases, including neurodegenerative37 and cardiovascular38 diseases. However, very little information is available regarding ASK1 and liver disease.39 This report shows the involvement of ASK1 in an in vivo liver disease model.
We showed that the ASK1–JNK pathway plays an important role in APAP-induced liver injury. In ASK1−/− mouse liver, APAP-induced prolonged JNK activation and liver injury was
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S.M. and M.O. were supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#17209026 and #19390205).