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

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

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

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