Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease
- 22 February 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 72 (5), 1617-1637
- https://doi.org/10.1002/hep.31197
Abstract
Alcohol‐associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no FDA‐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 non‐alcoholic fatty liver disease (NAFLD). However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells and mouse model systems. We demonstrated for the first time in liver specimens from alcoholic hepatitis (AH) patients, AR upregulation and elevated AR metabolites (sorbitol, fructose, and uric acid) which correlated significantly with (i) increased lipid peroxidation byproducts and ER stress, (ii) decreased protective ER chaperones, and (iii) greater cell death and liver injury. Further, 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. Lastly, we demonstrated the therapeutic potential of pharmacological AR inhibition against alcohol‐induced hepatic injury in experimental ALD Conclusions Our data demonstrate that hepatic AR upregulation, 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.Keywords
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