Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines

Shi,Changxuan; Wang,Yuanfang; Gao,Jing; Chen,Si; Zhao,Xiangqian; Cai,Chengchao; Guo,Chang; Qiu,Longxin

doi:10.3892/mmr.2017.6895

Inhibition of aldose reductase ameliorates alcoholic liver disease by activating AMPK and modulating oxidative stress and inflammatory cytokines

Authors:
- Changxuan Shi
- Yuanfang Wang
- Jing Gao
- Si Chen
- Xiangqian Zhao
- Chengchao Cai
- Chang Guo
- Longxin Qiu
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Affiliations: Department of Biological Science and Technology, School of Life Sciences, Longyan University, Longyan, Fujian 364012, P.R. China
Published online on: June 30, 2017 https://doi.org/10.3892/mmr.2017.6895
Pages: 2767-2772

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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.

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1	Ishii H, Kurose I and Kato S: Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress. J Gastroenterol Hepatol. 12:S272–S282. 1997. View Article : Google Scholar : PubMed/NCBI
2	Kawaratani H, Tsujimoto T, Douhara A, Takaya H, Moriya K, Namisaki T, Noguchi R, Yoshiji H, Fujimoto M and Fukui H: The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm. 2013:4951562013. View Article : Google Scholar : PubMed/NCBI
3	Hers HG: Aldose reductase. Biochim Biophys Acta. 37:120–126. 1960.(In French). View Article : Google Scholar : PubMed/NCBI
4	Nishimura-Yabe C: Aldose reductase in the polyol pathway: A potential target for the therapeutic intervention of diabetic complications. Nihon Yakurigaku Zasshi. 111:137–145. 1998.(In Japanese). View Article : Google Scholar : PubMed/NCBI
5	Brown KE, Broadhurst KA, Mathahs MM, Kladney RD, Fimmel CJ, Srivastava SK and Brunt EM: Immunodetection of aldose reductase in normal and diseased human liver. Histol Histopathol. 20:429–436. 2005.PubMed/NCBI
6	O'Connor T, Ireland LS, Harrison DJ and Hayes JD: 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 members. Biochem J. 343:487–504. 1999. View Article : Google Scholar : PubMed/NCBI
7	Qiu L, Lin J, Xu F, Gao Y, Zhang C, Liu Y, Luo Y and Yang JY: Inhibition of aldose reductase activates hepatic peroxisome proliferator-activated receptor-α and ameliorates hepatosteatosis in diabetic db/db mice. Exp Diabetes Res. 2012:7897302012. View Article : Google Scholar : PubMed/NCBI
8	Qiu L, Lin J, Ying M, Chen W, Yang J, Deng T, Chen J, Shi D and Yang JY: Aldose reductase is involved in the development of murine diet-induced nonalcoholic steatohepatitis. PLoS One. 8:e735912013. View Article : Google Scholar : PubMed/NCBI
9	Chen T, Shi D, Chen J, Yang Y, Qiu M, Wang W and Qiu L: Inhibition of aldose reductase ameliorates diet-induced nonalcoholic steatohepatitis in mice via modulating the phosphorylation of hepatic peroxisome proliferator-activated receptor α. Mol Med Rep. 11:303–308. 2015.PubMed/NCBI
10	Peng Z, Borea PA, Varani K, Wilder T, Yee H, Chiriboga L, Blackburn MR, Azzena G, Resta G and Cronstein BN: Adenosine signaling contributes to ethanol-induced fatty liver in mice. J Clin Invest. 119:582–594. 2009. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Lieber CS, DeCarli LM and Sorrell MF: Experimental methods of ethanol administration. Hepatology. 10:501–510. 1989. View Article : Google Scholar : PubMed/NCBI
13	Leung TM and Nieto N: CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease. J Hepatol. 58:395–398. 2013. View Article : Google Scholar : PubMed/NCBI
14	Lu Y and Cederbaum AI: CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med. 44:723–738. 2008. View Article : Google Scholar : PubMed/NCBI
15	You M, Matsumoto M, Pacold CM, Cho WK and Crabb DW: The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology. 127:1798–1808. 2004. View Article : Google Scholar : PubMed/NCBI
16	Sid B, Verrax J and Calderon PB: Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease. Biochem Pharmacol. 86:200–209. 2013. View Article : Google Scholar : PubMed/NCBI
17	Barry RE: Role of acetaldehyde in the pathogenesis of alcoholic liver disease. Br J Addict. 83:1381–1386. 1988. View Article : Google Scholar : PubMed/NCBI
18	Vander Jagt DL and Hunsaker LA: Substrate specificity of reduced and oxidized forms of human aldose reductase. Adv Exp Med Biol. 328:279–288. 1993. View Article : Google Scholar : PubMed/NCBI
19	Vander Jagt DL, Kolb NS, Vander Jagt TJ, Chino J, Martinez FJ, Hunsaker LA and Royer RE: Substrate specificity of human aldose reductase: Identification of 4-hydroxynonenal as an endogenous substrate. Biochim Biophys Acta. 1249:117–126. 1995. View Article : Google Scholar : PubMed/NCBI
20	Zhang C, Huang C, Tian Y and Li X: Polyol pathway exacerbated ischemia/reperfusion-induced injury in steatotic liver. Oxid Med Cell Longev. 2014:9636292014. View Article : Google Scholar : PubMed/NCBI
21	Ruef J, Liu SQ, Bode C, Tocchi M, Srivastava S, Runge MS and Bhatnagar A: Involvement of aldose reductase in vascular smooth muscle cell growth and lesion formation after arterial injury. Arterioscler Thromb Vasc Biol. 20:1745–1752. 2000. View Article : Google Scholar : PubMed/NCBI
22	Tracey WR, Magee WP, Ellery CA, MacAndrew JT, Smith AH, Knight DR and Oates PJ: Aldose reductase inhibition alone or combined with an adenosine A (3) agonist reduces ischemic myocardial injury. Am J Physiol Heart Circ Physiol. 279:H1447–H1452. 2000.PubMed/NCBI
23	Morimoto M, Hagbjörk AL, Nanji AA, Ingelman-Sundberg M, Lindros KO, Fu PC, Albano E and French SW: Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis. Alcohol. 10:459–464. 1993. View Article : Google Scholar : PubMed/NCBI
24	Viollet B, Guigas B, Leclerc J, Hébrard S, Lantier L, Mounier R, Andreelli F and Foretz M: AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives. Acta Physiol (Oxf). 196:81–98. 2009. View Article : Google Scholar : PubMed/NCBI
25	An L, Wang X and Cederbaum AI: Cytokines in alcoholic liver disease. Arch Toxicol. 86:1337–1348. 2012. View Article : Google Scholar : PubMed/NCBI
26	McClain CJ and Cohen DA: Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology. 9:349–351. 1989. View Article : Google Scholar : PubMed/NCBI
27	Endo M, Masaki T, Seike M and Yoshimatsu H: TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood). 232:614–621. 2007.PubMed/NCBI