NRF2 AKTİVATÖRÜ DİMETİL FUMARAT, AŞIRI ETANOL UYGULANAN SIÇANLARIN KARACİĞERİNDE YAĞLANMA, ENFLAMASYON VE LİPİD OKSİDASYONUNU AZALTTI

Year 2024, , 11 - 20, 29.01.2024

İlknur Bingül , Canan Küçükgergin , Asiye Işın Doğan Ekici , Semra Doğru Abbasoğlu , Müjdat Uysal

https://doi.org/10.26650/IUITFD.1344655

Abstract

Amaç: Bu çalışma, antioksidan ve anti-inflamatuar etkilere sahip dimetil fumaratın (DMF) sıçanlarda binge etanol (EtOH) ile indüklenen karaciğer steatozu, inflamasyon ve lipit peroksidasyonu üzerindeki etkisini araştırmak amacıyla yapıldı.
Gereç ve Yöntem: EtOH ile indüklenen karaciğer hasarına karşı DMF'nin potansiyel koruyucu etkisini incelemek için sıçanlar kontrol, DMF, EtOH ve DMF+EtOH olmak üzere dört gruba ayrıldı. Sıçanlara EtOH (4,5 g/kg oral, 12 saat arayla 3 doz) verildi. DMF+EtOH grubundaki sıçanlara her EtOH uygulamasından 1 saat önce DMF (30 mg/kg; gavaj) uygulandı. Karaciğer hasarı serum belirteçleri, trigliserid (TG), tümör nekroz faktörü-alfa (TNF-α), lipid ve protein oksidasyon ürünleri, miyeloperoksidaz (MPO) ve antioksidan enzimler ile birlikte karaciğer dokusunda histopatolojik incelemeler gerçekleştirildi. Karaciğerde antioksidan mekanizma (nükleer faktör eritroid 2 ile ilişkili faktör; Nrf2 ve hem oksijenaz-1; HO-1), lipid metabolizması (sterol düzenleyici element bağlayıcı protein-1c; SREBP-1c ve peroksizom proliferatör ile aktive olan reseptör-alfa; PPAR-α) oksidatif stres (sitokrom P4502E1; CYP2E1) ve inflamasyon (nükleer faktör-kappa B; NF- κB) ile ilişkili protein ekspresyonları da araştırıldı.
Bulgular: DMF, EtOH uygulanan sıçanlarda histopatolojik lezyonların iyileşmesinin yanında artmış serum karaciğer hasarı belirteçlerini, hepatik TG, TNF-α ve reaktif oksijen türleri düzeylerini, lipid ve protein oksidasyon ürünlerini ve MPO aktivitesini de azalttı. DMF+EtOH grubunda Nrf2 ve HO-1ekspresyonlarının EtOH grubuna göre arttığı ve SREBP-1c ve CYP2E1 ekspresyonlarının ise EtOH grubuna göre azaldığı saptandı.
Sonuç: Sonuçlarımız, DMF'nin EtOH tarafından indüklenen karaciğer lezyonlarının oluşumuna karşı koruyucu bir etki sağlayabileceğini göstermektedir. Bu etkiler, DMF ile indüklenen Nrf2 aktivasyonunun antioksidan, anti-inflamatuar ve anti-lipojenik potansiyeli ile ilişkili olabilir.

Keywords

Dimetil fumarat, nükleer faktör eritroid 2 ilişkili faktör, etanol, karaciğer hasarı, oksidatif stres

Project Number

119S932

NRF2 ACTIVATOR DIMETHYL FUMARATE DIMINISHED STEATOSIS, INFLAMMATION AND LIPID PEROXIDATION IN THE LIVER OF BINGE ETHANOL-TREATED RATS

Abstract

Objective: This study was conducted to explore the impact of dimethyl fumarate (DMF), which has antioxidant and anti-inflammatory effects, on binge ethanol (EtOH)-induced hepatic steatosis, inflammation, and lipid peroxidation in rats.
Material and Method: To examine the potential protective effect of DMF against EtOH-induced hepatic damage, rats were divided into four groups control, DMF, EtOH, and DMF+EtOH. Rats were administered EtOH (4.5 g/kg orally, 3 doses with 12-h intervals). DMF (30 mg/kg; gavage) was applied to rats 1 hour before each application of EtOH in the DMF+EtOH group. Serum markers of liver damage, triglyceride (TG), tumor necrosis factor-alpha (TNF-α), lipid and protein oxidation products, myeloperoxidase (MPO), and antioxidant enzymes together with histopathological examinations were performed in liver tissue. Protein expressions associated with antioxidant mechanism (nuclear factor erythroid 2-related factor; Nrf2 and heme oxygenase- 1; HO-1), lipid metabolism (sterol regulatory element-binding protein-1c; SREBP-1c and peroxisome proliferator-activated receptor-alpha; PPAR-α), oxidative stress (cytochrome P4502E1; CYP2E1), and inflammation (nuclear factor-kappa B; NF-κB) were also investigated in the rats’ livers.
Result: DMF reduced elevated levels of serum markers of liver damage and hepatic TG, TNF-α and reactive oxygen species levels, lipid and protein oxidation products, and MPO activity together with the alleviation of histopathological lesions in EtOH-treated rats. Increased Nrf2 and HO-1 and decreased SREBP-1c and CYP2E1 expressions were also detected in the DMF+EtOH group compared with the EtOH group.
Conclusion: Our results demonstrate that DMF may provide a protective effect against EtOH-induced hepatic lesions. These outcomes may be linked to the anti-oxidative, anti-inflammatory, and anti-lipogenic potential of DMF-induced Nrf2 activation.

Keywords

Dimethyl fumarate, nuclear factor erythroid 2-related factor, ethanol, liver damage, oxidative stress

Supporting Institution

The present work was supported by Scientific and Technological Research Council of Turkey (TUBITAK).

Project Number

119S932

References

• Hyun J, Han J, Lee C, Yoon M, Jung Y. Pathophysiological aspects of alcohol metabolism in the liver. Int J Mol Sci 2021;22(11):5717. [CrossRef] google scholar
• Namachivayam A, Valsala Gopalakrishnan A. A review on molecular mechanism of alcoholic liver disease. Life Sci 2021;274:119328. [CrossRef] google scholar
• Sakaguchi S, Takahashi S, Sasaki T, Kumagai T, Nagata K. Progression of alcoholic and non-alcoholic steatohepatitis: common metabolic aspects of innate immune system and oxidative stress. Drug Metab Pharmacokinet 2011;26(1):30-46. [CrossRef] google scholar
• Huang Y, Li W, Su ZY, Kong ANT. The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 2015;26(12):1401-13. [CrossRef] google scholar
• Huang J, Tabbi-Anneni I, Gunda V, Wang L. Transcription factor Nrf2 regulates SHP and lipogenic gene expression in hepatic lipid metabolism. Am J Physiol Gastrointest Liver Physiol 2010;299(6): G1211-21. [CrossRef] google scholar
• Huang QH, Xu LQ, Liu YH, Wu JZ, Wu X, Lai XP, et al. Polydatin protects rat liver against ethanol-induced injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-kB p65 pathway. Evid Based Complement Alternat Med 2017;2017:7953850. [CrossRef] google scholar
• Jadeja RN, Upadhyay KK, Devkar RV, Khurana S. Naturally occurring Nrf2 activators: Potential in treatment of liver injury. Oxid Med Cell Longev 2016;2016:3453926. [CrossRef] google scholar
• Zhou J, Zheng Q, Chen Z. The Nrf2 pathway in liver diseases. Front Cell Dev Biol 2022;10:826204. [CrossRef] google scholar
• Sun J, Fu J, Li L, Chen C, Wang H, Hou Y, et al. Nrf2 in alcoholic liver disease. Toxicol Appl Pharmacol 2018;357:62-9. [CrossRef] google scholar
• Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 2018;75(17):3143-57. [CrossRef] google scholar
• More VR, Cheng Q, Donepudi AC, Buckley DB, Lu ZJ, Cherrington NJ, et al. Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. Drug Metab Dispos 2013;41(5):1148-55. [CrossRef] google scholar
• Wang Z, Dou X, Li S, Zhang X, Sun X, Zhou Z, et al. Nuclear factor (erythroid-derived 2)-like 2 activation-induced hepatic very-low-density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice. Hepatology 2014;59(4):1381-92. [CrossRef] google scholar
• Kourakis S, Timpani CA, DeHaan JB, Gueven N, Fischer D, Rybalka E. Dimethyl fumarate and its esters: A drug with broad clinical utility? Pharmaceuticals 2020;13(10):306. [CrossRef] google scholar
• Ibrahim SG, El-Emam SZ, Mohamed EA, Abd Ellah MF. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties. Int Immunopharmacol 2020;80:106131. [CrossRef] google scholar
• Dwivedi DK, Jena G, Kumar V. Dimethyl fumarate protects thioacetamide-induced liver damage in rats: Studies on Nrf2, NLRP3, and NF-kB. J Biochem Mol Toxicol 2020;34(6):e22476. [CrossRef] google scholar
• Mostafa ME, Shaaban AA, Salem H.A. Dimethylfumarate ameliorates hepatic injury and fibrosis induced by carbon tetrachloride. Chem Biol Interact 2019;302:53-60. [CrossRef] google scholar
• Sun J, Fu J, Zhong Y, Li L, Chen C, Wang, X, et. al. NRF2 mitigates acute alcohol-induced hepatic and pancreatic injury in mice. Food Chem Toxicol 2018;121:495-503. [CrossRef] google scholar
• Sangineto M, Grabherr F, Adolph TE, Grander C, Reider S, Jaschke N, et. al. Dimethyl fumarate ameliorates hepatic inflammation in alcohol related liver disease. Liver Int 2020;40(7):1610-9. [CrossRef] google scholar
• Zhang Y, Zhao S, Fu Y, Yan L, Feng Y, Chen Y, et al. Computational repositioning of dimethyl fumarate for treating alcoholic liver disease. Cell Death Dis 2020;11(8):641. [CrossRef] google scholar
• Artun BC, Küskü-Kiraz Z, Güllüoğlu M, Çevikbaş U, Koçak-Toker N, Uysal M. The effect of carnosine pretreatment on oxidative stress and hepatotoxicity in binge ethanol administered rats. Hum Exp Toxicol 2010;29(8):659-65. [CrossRef] google scholar
• Kirpich I, Ghare S, Zhang J, Gobejishvili L, Kharebava G, Barve SJ, et al. Binge alcohol-induced microvesicular liver steatosis and injury are associated with down-regulation of hepatic Hdac 1,7,9,10,11 and up-regulation of Hdac 3. Alcohol Clin Exp Res 2012;36(9):1578-86. [CrossRef] google scholar
• Rachmilewitz D, Stamler JS, Karmeli F, Mullins ME, Singel DJ, Loscalzo J, et al. Peroxynitrite-induced rat colitis - a new model of colonic inflammation. Gastroenterology 1993;105(6):1681-8. [CrossRef] google scholar Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302-10. [CrossRef] google scholar
• Hanasand M, Omdal R, Norheim KB, G0ransson LG, Brede C, Jonsson G. Improved detection of advanced oxidation protein products in plasma. Clin Chim Acta 2012;413(9-10):901-6. [CrossRef] google scholar
• Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8. google scholar
• Mylorie AA, Collins H, Umbles C, Kyle J. Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol 1986;82(3):512-20. [CrossRef] google scholar
• Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976;71:952-8. [CrossRef] google scholar
• Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985;150(1):76-85. [CrossRef] google scholar
• Ghosh Dastidar S, Warne JB, Warner DR, McClain CJ, Kirpich IA. Rodent models of alcoholic liver disease: Role of binge ethanol administration. Biomolecules 2018;8(1):3. [CrossRef] google scholar
• Choi BK, Kim TW, Lee DR, Jung WH, Lim JH, Jung JY, et al. A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model. Phytother Res 2015;29:1577-84. [CrossRef] google scholar
• Huang QH, Xu LQ, Liu YH, Wu JZ, Wu X, Lai XP, et al. Polydatin protects rat liver against ethanol-induced injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-kB p65 pathway. Evid Based Complement Alternat Med 2017;2017:7953850. [CrossRef] google scholar
• Sim WC, Yin HQ, Choi HS, Choi YJ, Kwak H, Kim SK, et al. L-serine supplementation attenuates alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. J Nutr 2015;145(2):260-267. [CrossRef] google scholar
• Lei P, Zhao W, Pang B, Yang X, Li BL, Ren M, et al. Broccoli sprout extract alleviates alcohol-induced oxidative stress and endoplasmic reticulum stress in C57BL/6 mice. J Agric Food Chem 2018;66(22):5574-80. [CrossRef] google scholar
• Li XX, Jiang ZH, Zhou B, Chen C, Zhang XY. Hepatoprotective effect of gastrodin against alcohol-induced liver injury in mice. J Physiol Biochem 2019;75(1):29-37. [CrossRef] google scholar
• Zhou R, Lin J, Wu D. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochim Biophys Acta 2014;1840(1):209-18. [CrossRef] google scholar
• Gong P, Cederbaum AI. Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1. Hepatology 2006;43(1):144-53. [CrossRef] google scholar
• Yeligar SM, Machida K, Kalra VK. Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem 2010;285(46):35359-73. [CrossRef] google scholar
• Origassa CS, Amara, NOS. Cytoprotective role of heme oxygenase-1 and heme degradation derived end products in liver injury. World J Hepatol 2013;5(10):541-9. [CrossRef] google scholar
• Vanani AR, Kalantari H, Mahdavinia M, Rashno M, Khorsandi L, Khodayar MJ. Dimethyl fumarate reduces oxidative stress, inflammation and fat deposition by modulation of Nrf2, SREBP-1c and NF-κB signaling in HFD fed mice. Life Sci 2021;283:119852. [CrossRef] google scholar
• Dwivedi DK, Jena GB. Dimethyl fumarate-mediated Nrf2/ ARE pathway activation and glibenclamide-mediated NLRP3 inflammasome cascade inhibition alleviate type II diabetes-associated fatty liver in rats by mitigating oxidative stress and inflammation. Biochem Mol Toxicol. 2023;37(7):e23357. [CrossRef] google scholar