Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease

PLoS One. 2013 Jul 26;8(7):e70034. doi: 10.1371/journal.pone.0070034. Print 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaldehyde / metabolism*
  • Aldehydes / analysis
  • Animals
  • Cells, Cultured
  • Ethanol / administration & dosage
  • Ethanol / metabolism
  • Glutathione / analysis
  • Glutathione / metabolism
  • Glycation End Products, Advanced / analysis
  • Glycation End Products, Advanced / metabolism*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Liver / metabolism
  • Liver / pathology*
  • Liver Diseases, Alcoholic / blood
  • Liver Diseases, Alcoholic / metabolism*
  • Liver Diseases, Alcoholic / pathology*
  • Male
  • Rats
  • Rats, Wistar

Substances

  • Aldehydes
  • Glycation End Products, Advanced
  • Ethanol
  • Glutathione
  • Acetaldehyde
  • 4-hydroxy-2-nonenal

Grant support

This work was supported in part by grants from the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (B)], #22300264 (MT2) and by Grant No. SR2012-04 (MT) for research from Kanazawa Medical University, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.