Acetaldehyde-Derived Advanced Glycation End-Products Promote Alcoholic Liver Disease

Abstract

BackgroundChronic 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).MethodsRat 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.ResultsHepatocyte 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.ConclusionsThe 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.

Effect of imidazoline‐1 receptor agonists on renal dysfunction in rats associated with chronic, sequential fructose and ethanol administration

“…Additionally, a study by Teichert et al showed that sAGE levels increased in the early stages of impaired glucose homeostasis. In the same context, chronic ethanol consumption induces metabolic changes, such as hyperlipidaemia and hyperglycaemia, and increases circulating AGEs …”

“…Metabolic changes caused by chronic ethanol consumption, such as hyperlipidaemia, insulin resistance and increased circulating levels of advanced glycation end products (AGEs), contribute to renal dysfunction. Lipoproteins can mediate nephrotoxicity by inducing oxidative stress and pro‐inflammatory cytokine expression .…”

Hepatotoxicity of Reactive Aldehydes☆

“…Data from this study demonstrated that AA-AGE is toxic to hepatocytes, but that N-ethyllysine was not. Additionally, chronic ingestion of ethanol produced oxidative stress, AA-AGE and 4HNE staining that all correlated with the degree of alcoholic liver disease in both rodent and human liver tissue (Hayashi et al, 2013).…”

Current evidence on the use of probiotics in liver diseases

“…Furthermore, chronic ingestion of ethanol increases acetaldehyde, a major toxic metabolic intermediate of alcohol detoxification that causes direct DNA damage, leads to the production of several end-products which contribute to the pathogenesis of ALD (Hayashi et al, 2013). …”