Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease

Abstract

Background and Aims Alcohol‐associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no Food and Drug Administration–approved therapies. Fructose (dietary or endogenous), its metabolite uric acid, and aldose reductase (AR, the only endogenous enzyme that produces fructose) are strongly associated with the development of nonalcoholic fatty liver disease. However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells, and mouse model systems. Approach and Results We demonstrated in liver specimens from patients with alcoholic hepatitis, the AR up‐regulation and elevated AR metabolites (sorbitol, fructose, and uric acid), which correlated significantly with (1) increased lipid peroxidation byproducts and endoplasmic reticulum (ER) stress, (2) decreased protective ER chaperones, and (3) greater cell death and liver injury. Furthermore, we established a causal role for AR in ALD by showing that the genetic deficiency of AR (knockout mice) prevented alcohol‐induced increase in harmful AR metabolites, toxic aldehydes, steatosis, ER stress, apoptosis, and liver injury. Finally, we demonstrated the therapeutic potential of pharmacological AR inhibition against alcohol‐induced hepatic injury in experimental ALD. Conclusions Our data demonstrate that hepatic AR up‐regulation, and consequent elevation in fructose, sorbitol and/or uric acid, are important factors contributing to alcohol‐induced steatosis, ER stress, apoptosis, and liver injury in both experimental and human ALD. Our study provides a strong rationale to evaluate AR as a potential therapeutic target and to test AR inhibitors to ameliorate alcohol‐induced liver injury.

Does the breakdown of the detoxification system for aldehydes as a result of aldose reductase upregulation lead to alcohol‐induced liver injury in humans and mice?

“…The first novel observation of Wang et al 7 in their study using liver specimens from AH patients found that marked upregulation of AR corresponded with the elevation of AR metabolites (hepatic sorbitol, fructose and uric acid). More importantly, they observed a strong positive correlation between AR upregulation with AR metabolites and the endoplasmic reticulum (ER) stress markers activating transcription factor 3 (ATF3) and CCAAT/enhancer-binding protein homologous protein (CHOP), and a significant negative correlation with the protective chaperone proteins glucoseregulated protein (GRP)78 and GRP94 in the AH patients' livers.…”

“…In primary hepatocytes, either fructose or uric acid attenuated cell viability, and also markedly upregulated ATF3 and CHOP. It is interesting and valuable that AR upregulation was observed as a result of exposure to fructose or uric acid, indicating a kind of a feed-forward mechanism 7 . The observation of this mechanism induced by AR metabolites seems to be highly significant in consideration of a trigger for AR upregulation caused by alcohol.…”

“…In any case, both ALD and NAFLD are closely related with diabetes, making it desirable to develop an effective medicine to treat them. Recent studies of ALD using animals [5][6][7] and humans 7 give us a ray of hope. These studies approach the mechanisms of alcohol-induced hepatic injury from the perspective of the polyol pathway.…”

“…Recently, Wang et al 7 showed the role of AR in ALD involving therapeutic targets by using human specimens, cultured cells and animal models, including ARKO mice. In liver specimens from alcoholic hepatitis (AH) patients, they found AR upregulation and increased AR metabolites (sorbitol, fructose and uric acid).…”

“…In their study to definitely establish the causal role of AR upregulation in ALD, Wang et al 7 investigated using ARdeficient ARKO mice or the pharmacological inhibition of AR. Alcohol-mediated AR upregulation with increased AR metabolites (hepatic sorbitol and fructose, and serum uric acid) in alcohol-fed wild type (WT) mice was reduced in ARKO mice.…”