Ethanol-induced JNK activation suppressed via active Akt in hepatocytes.
Ethanol induces c-Jun N-terminal kinase (JNK) activation leading to cell death in hepatocytes. However, acute alcohol exposure does not induce remarked cell death in hepatocytes. We hypothesized that active Akt may suppress JNK activation. To clarify this point, we evaluated the role of active Akt in JNK activation under treatment with hepatocyte growth factor (HGF) and compared it with ethanol treatment. Primary rat hepatocytes were treated with 10 ng/ml HGF. 10 min after that, 5 microM insulin, an activator of the Akt pathway, and/or 5 microM LY294002, an inhibitor of the pathway, were added. Hepatocytes were treated with 100 mM ethanol and LY294002. HGF treatment increased JNK activities in hepatocytes. This JNK activation was accumulated by addition of LY294002. These finding suggest that active Akt suppresses JNK activation induced by HGF. On the other hand, addition of insulin did not decrease the JNK activity, showing that insulin-induced Akt activation may rather increase JNK activity. Ethanol also induced JNK activation and this JNK activation was enhanced by LY294002 similar to HGF treatment. We found that active Akt suppressed JNK activation induced by ethanol as well as HGF in hepatocytes. JNK activation may be suppressed by prolonged active Akt or basal active Akt, rather than peaked activation of Akt induced by insulin stimulation. Our results suggest that the suppression of JNK by active Akt may prevent cell death in acute alcohol intoxication.
Nishitani
Yoko
Y
Department of Legal Medicine and Molecular Alcohology, Sapporo Medical University School of Medicine, S-1 W-17, Sapporo 060-8556, Japan.
Okazaki
Sunichiro
S
Imabayashi
Kiyomi
K
Katada
Ryuichi
R
Matsumoto
Hiroshi
H
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000009:adverse effects* / Q000506:poisoning; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000431:Ethanol; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases