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

Öz

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.

Anahtar Kelimeler

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

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

Öz

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.

Anahtar Kelimeler

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

Kaynakça

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