Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines
- 1 March 2017
- journal article
- Published by Spandidos Publications in Molecular Medicine Reports
- Vol. 16 (3), 2767-2772
- https://doi.org/10.3892/mmr.2017.6895
Abstract
Aldose reductase (AR) expression is elevated in the livers of patients with alcoholic liver diseases. However, the role of AR in the development of alcoholic liver diseases remains unclear. The aim of the present study was to determine the effect of AR inhibition on ethanol‑induced hepatosteatosis in vivo and in vitro, and to identify possible underlying molecular mechanisms. Alcoholic fatty livers were induced in C57BL/6 mice by feeding the mice with Lieber‑DeCarli liquid diets. The expression of AR protein was elevated in the liver tissue of C57BL/6 mice fed with an ethanol diet and in mouse AML12 liver cells exposed to ethanol. In addition to the elevation in AR, hepatic steatosis was observed in ethanol diet‑fed mice, and this ethanol‑induced steatosis was significantly attenuated by inhibiting AR activity with a specific inhibitor, zopolrestat. The suppressive effect of AR inhibition was associated with decreased levels of hepatic lipoperoxides, decreased protein expression of hepatic cytochrome P450 2E1 (CYP2E1), increased phosphorylation of 5'‑AMP‑activated protein kinase (AMPK) and decreased mRNA expression of tumor necrosis factor‑α (TNF‑α). Treatment with the AR inhibitor attenuated the level of lipid accumulation and oxidative stress, activated AMPK, and suppressed the mRNA expression of TNF‑α, interleukin‑6 and transforming growth factor‑β1 in ethanol‑treated AML12 cells. The results of the present study demonstrated that inhibition of AR ameliorated alcoholic liver disease in vivo and in vitro, in part by activating AMPK, decreasing CYP2E1‑mediated oxidative stress and ameliorating the expression of pro‑inflammatory cytokines.Keywords
This publication has 24 references indexed in Scilit:
- Inhibition of aldose reductase ameliorates diet-induced nonalcoholic steatohepatitis in mice via modulating the phosphorylation of hepatic peroxisome proliferator-activated receptor αMolecular Medicine Reports, 2014
- The Effect of Inflammatory Cytokines in Alcoholic Liver DiseaseMediators of Inflammation, 2013
- Aldose Reductase Is Involved in the Development of Murine Diet-Induced Nonalcoholic SteatohepatitisPLOS ONE, 2013
- Inhibition of Aldose Reductase Activates Hepatic Peroxisome Proliferator-Activated Receptor-αand Ameliorates Hepatosteatosis in Diabetic db/db MiceExperimental Diabetes Research, 2012
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family membersBiochemical Journal, 1999
- [Aldose reductase in the polyol pathway: a potential target for the therapeutic intervention of diabetic complications].Folia Pharmacologica Japonica, 1998
- Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stressJournal of Gastroenterology and Hepatology, 1997
- Experimental methods of ethanol administrationHepatology, 1989
- L'aldose-réductaseBiochimica et Biophysica Acta, 1960