Neuregulin-4 as a novel target of dapagliflozin in high-fat diet-induced fatty liver disease in rats

Objective: The present study aimed to evaluate the hepatoprotective effects of dapagliflozin in a rat model of high-fat/high-fructose diet-induced fatty liver disease and to investigate its association with Neuregulin-4 (NRG4) expression. Methods: Forty adult male Wistar albino rats were randomly allocated into five groups (n = 8 each): control, high-fat/high-fructose diet (HFD), pioglitazone-treated (10 mg/kg/day + HFD), dapagliflozin-treated (1 mg/kg/day + HFD), and vehicle-treated (1% DMSO + HFD). Pioglitazone and dapagliflozin were administered orally for 14 days before induction and continued throughout the 8-week induction period. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, while hepatic malondialdehyde (MDA), reduced glutathione (GSH), and NRG4 levels were determined using ELISA-based methods. Histopathological and fibrosis assessments were performed using hematoxylin and eosin and Masson's trichrome staining. Results: The HFD group demonstrated significant hepatic injury, characterised by increased serum ALT, AST, and hepatic MDA levels, together with reduced GSH and NRG4 levels compared with the control group. Treatment with dapagliflozin significantly improved liver enzyme profiles, attenuated oxidative stress, restored antioxidant status, and increased hepatic NRG4 levels. Histopathological examination revealed a marked reduction in hepatic steatosis and fibrosis in dapagliflozin-treated rats, with effects comparable to those observed with pioglitazone treatment. Conclusion: Dapagliflozin administration was associated with improvement of biochemical, oxidative stress, and histopathological alterations induced by a high-fat/high-fructose diet in rats. The findings are consistent with a potential role of NRG4 in the hepatoprotective effects of dapagliflozin; however, further mechanistic studies are required to clarify the underlying molecular pathways.