Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease.
BACKGROUND
Chronic ingestion of ethanol increases acetaldehyde and leads to the production of acetaldehyde-derived advanced glycation end-products (AA-AGE). We evaluated the toxicity of AA-AGE on hepatocytes and studied the role of AA-AGE in the pathogenesis of alcoholic liver disease (ALD).


METHODS
Rat hepatocyte cultures were treated with N-ethyllysine (NEL) or AA-AGE and the cell viability was evaluated using MTT assay. Male Wistar rats were fed with liquid diet containing 5% ethanol for 8 weeks following normal diet for another 12 weeks. A group of animals was sacrificed at 4th, 6th, and 8th week and the remaining animals at 12th, 14th, 16th, 18th, and 20th week. The liver sections were stained for AA-AGE and 4-hydroxy-2-nonenal (4-HNE). Liver biopsy obtained from ALD patients was also stained for AA-AGE and 4-HNE.


RESULTS
Hepatocyte viability was significantly reduced in cultures treated with AA-AGE compared to NEL treated or control cultures. Severe fatty degeneration was observed during chronic administration of ethanol increasing from 4-8 weeks. The staining of AA-AGE and 4-HNE was correlated with the degree of ALD in both rat and human. In rats, hepatic fatty degeneration was completely disappeared and the staining for both AA-AGE and 4-HNE returned to normal at 12th week of abstinence. Staining for AA-AGE and 4-HNE was completely absent in normal human liver.


CONCLUSIONS
The data demonstrated that AA-AGE is toxic to hepatocytes, but not NEL. Chronic ethanol ingestion produces AA-AGE and reactive oxygen species that contribute to the pathogenesis of ALD. Abstinence of alcohol results in complete disappearance of both AA-AGE and 4-HNE along with fatty degeneration suggesting that AA-AGE plays a significant role in the pathogenesis of ALD.
Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
Nobuhiko
N
Hayashi
Joseph
J
George
Masayoshi
M
Takeuchi
Atsushi
A
Fukumura
Nobuyuki
N
Toshikuni
Tomiyasu
T
Arisawa
Mikihiro
M
Tsutsumi
D000079:Acetaldehyde / Q000378:metabolism*; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D002478:Cells, Cultured; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D017127:Glycation End Products, Advanced; D000431:Ethanol; D005978:Glutathione; D000079:Acetaldehyde; C027576:4-hydroxy-2-nonenal