Abstract
Dapagliflozin is a selective sodium-glucose cotransporter-2 (SGLT2) inhibitor that has emerged a one of the most important therapeutic advances in the management of metabolic, cardiovascular, and renal diseases. This study aims to investigate the protective effect of dapagliflozin on hepatic oxidative stress, antioxidant defense systems, and mitochondrial biogenesis in a high-fat-diet (HFD)-induced rat model, with particular emphasis on its ability to ameliorate metabolic disturbances and preserve liver function through modulation of oxidative and mitochondrial pathways. Totally, 60 adult male Wistar rats were purchased, acclimated, and divided equally to four groups including NDC (fed pellets only), HFDC (fed pellets plus 10% lard, 2% cholesterol, and 0.3% bile salts, HFD-D (fed HFD pellets and received dapagliflozin only), HFD-DE (fed HFD pellets with receiving dapagliflozin and vitamin E) after 30 days, all study rats were euthanized, and subjected to collection of blood and liver tissues to assessment biochemical parameters, hepatic antioxidant enzyme activity, lipid peroxidation, ATP production, and citrate synthase activity. Liver tissue was also analyzed to determine mitochondrial biogenesis with PGC-1α gene expression quantification using RT-qPCR. The findings indicated that a high-fat diet significantly (p<0.05) elevated of serum ALT, AST, triglycerides, MDA, and a decrease of SOD, CAT, GPx, GSH, ATP, and citrate synthase activities (p<0.05). Decreases in antioxidant status and mitochondrial functional indices associated with both doses of dapagliflozin were reversed, while the high dose induced vitamin E equivalents effects. With dapagliflozin, a significant elevation of hepatic PGC-1α expression compared to high-fat diet alone was also noted (p<0.05). In conclusion, the findings suggest that dapagliflozin may enhance antioxidant defenses and mitochondrial function under high-fat diet conditions.

Key words: Glucose-lowering drug, Hepatic activity, Iraq, Lipid peroxidation, Oxidative stress