Wang Min, Chen Wei-Yang, Zhang Jingwen, Gobejishvili Leila, Barve Shirish S, McClain Craig J, Joshi-Barve Swati
Department of Medicine, University of Louisville, Louisville, KY.
Alcohol Research Center, University of Louisville, Louisville, KY.
Hepatology. 2020 Nov;72(5):1617-1637. doi: 10.1002/hep.31197. Epub 2020 Oct 15.
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.
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.
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.
酒精性肝病（ALD）是一种在全球范围内常见的慢性肝病，发病率和死亡率都很高，且尚无美国食品药品监督管理局批准的治疗方法。果糖（饮食中的或内源性的）、其代谢产物尿酸以及醛糖还原酶（AR，唯一产生果糖的内源性酶）与非酒精性脂肪性肝病的发生密切相关。然而，AR或其代谢产物在ALD中的作用仍未得到充分研究，我们使用人类标本、培养细胞和小鼠模型系统对此进行了研究。
我们在酒精性肝炎患者的肝脏标本中发现，AR上调且AR代谢产物（山梨醇、果糖和尿酸）升高，这与以下情况显著相关：（1）脂质过氧化副产物和内质网（ER）应激增加；（2）保护性ER伴侣蛋白减少；（3）细胞死亡和肝损伤加剧。此外，我们通过证明AR基因缺陷（基因敲除小鼠）可预防酒精诱导的有害AR代谢产物、有毒醛类、脂肪变性、ER应激、细胞凋亡和肝损伤增加，确定了AR在ALD中的因果作用。最后，我们证明了在实验性ALD中，药理学抑制AR对酒精诱导的肝损伤具有治疗潜力。
我们的数据表明，肝脏AR上调以及随之而来的果糖、山梨醇和/或尿酸升高，是导致实验性和人类ALD中酒精诱导的脂肪变性、ER应激、细胞凋亡和肝损伤的重要因素。我们的研究为评估AR作为潜在治疗靶点以及测试AR抑制剂以改善酒精诱导的肝损伤提供了有力的理论依据。
