Fructose, its metabolite uric acid, and aldose reductase (AR) are strongly implicated in the development of nonalcoholic fatty liver disease (NAFLD). The role of AR or its metabolites is not clearly known in ALD. Investigators recently evaluated the role of AR or its metabolites in ALD with the help of human specimens, cultured cells and mouse models.

It was shown for the first time in liver specimens from alcoholic hepatitis (AH) patients that AR was upregulated and AR metabolites were raised (sorbitol, fructose, and uric acid) which had a significant correlation with:

• raised lipid peroxidation byproducts and ER stress,
• reduction in protective ER chaperones, and
• greater cell death and liver injury.

Investigators identified a causal role for AR in ALD as they demonstrated that the genetic deficiency of AR (knockout mice) prevented the alcohol-induced elevation in deleterious AR metabolites, toxic aldehydes, steatosis, ER stress, apoptosis and liver injury.

The study also noted the therapeutic potential of pharmacological inhibition of AR against alcohol-induced hepatic injury in experimental ALD.

Hepatic AR upregulation and the rise in fructose, sorbitol and/or uric acid contribute to alcohol-induced steatosis, ER stress, apoptosis and liver injury in experimental as well as human ALD. AR must therefore be assessed as a potential therapeutic target and AR inhibitors should be evaluated in alcohol-induced liver injury.

Source: Wang M, Chen W-Y, Zhang J, et al. Elevated fructose and uric acid via aldose reductase contribute to experimental and human alcoholic liver disease. Hepatology 22 February 2020 https://doi.org/10.1002/hep.31197.