Inhibition of 5-Lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model

Document Type : Original Article

Authors

The First Affiliated Hospital, Zhejiang University；79# Qingchun Road, Hangzhou 310003, China

Abstract

Objective(s): Arachidonic Acid/5-lipoxygenase (AA/5-LOX) pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD). Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model.
Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD). Liver function, HE staining, NAFLD activity score (NAS) were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA) and AA, products: cysteinyl-leukotrienes (CysLTs), and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-yl)ethyl]-1-hydroxyurea) was administrated.
Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE) staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS.
Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

Keywords

References

1. Koo SH. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol 2013;19:210-215.
2. Verbeek J, Cassiman D, Lannoo M, Laleman W, van der Merwe S, Verslype C, et al. Treatment of non-alcoholic fatty liver disease: can we already face the epidemic? Acta Gastroenterol Belg 2013;76:200-209.
3. Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J nutr biochem 2008;19:567-576.
4. Shimomura Y, Takaki A, Wada N, Yasunaka T, Ikeda F, Maruyama T, et al. The serum oxidative/anti-oxidative stress balance becomes dysregulated in patients with non-alcoholic steatohepatitis associated with hepatocellular carcinoma. Intern Med 2017;56:243-251.
5. Ayd N S, Atukeren PN, Akatay U, Uzun H, Altu T. Gender-dependent oxidative variations in liver of aged rats. BIOGERONTOLOGY 2010;11:335-346.
6.  Nakamura Y, Kozuka M, Naniwa K, Takabayashi S, Torikai K, Hayashi R, et al. Arachidonic acid cascade inhibitors modulate phorbol ester-induced oxidative stress in female ICR mouse skin: differential roles of 5-lipoxygenase and cyclooxygenase-2 in leukocyte infiltration and activation. Free Radic Biol Med 2003;35:997-1007.
7. Colak Y, Senates E, Ozturk O, Doganay HL, Coskunpinar E, Oltulu YM, et al. Association of serum lipoprotein-associated phospholipase A2 level with nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2012;10:103-109.
8. Carmiel-Haggai M, Cederbaum AI, Nieto N. A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. faseb J 2005;19:136-138.
9. Xu XM, Deng JJ, Yuan GJ, Yang F, Guo HT, Xiang M, et al. 5-Lipoxygenase contributes to the progression of hepatocellular carcinoma. mol med rep 2011;4:1195-200.
10. Martinez-Clemente M, Claria J, Titos E. The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease. Curr Opin Clin Nutr Metab Care 2011;14:347-353.
11. Back M. Inhibitors of the 5-lipoxygenase pathway in atherosclerosis. Curr Pharm Des 2009;15:3116-3132.
12. Cingi C, Muluk NB, Ipci K, Sahin E. Antileukotrienes in upper airway inflammatory diseases. Curr Allergy Asthma Rep 2015;15:64.
13. Zhou GX, Ding XL, Wu SB, Zhang HF, Cao W, Qu LS, et al. Inhibition of 5-lipoxygenase triggers apoptosis in pancreatic cancer cells. oncol rep 2015;33:661-668.
14. Collin M, Rossi A, Cuzzocrea S, Patel NS, Di Paola R, Hadley J, et al. Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton. J Leukoc Biol 2004;76:961-970.
15. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. hepatology 2005;41:1313-1321.
16. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. int J exp pathol 2006;87:1-16.
17. Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Faliva M, Perna S, et al. Correlation of the controlled attenuation parameter with indices of liver steatosis in overweight or obese individuals: a pilot study. Eur J Gastroenterol Hepatol 2015;27:305-312.
18. Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Faliva M, Perna S, et al. Correlation of the controlled attenuation parameter with indices of liver steatosis in overweight or obese individuals. eur J gastroen hepat 2015;27:305-312.
Iranian Journal of Basic Medical Sciences
Volume 20, Issue 11
November 2017
Pages 1207-1212

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