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Abstract Hepatic steatosis (storing excess amount of fats in the liver ) is the primary stage in a variety of liver diseases called NAFLD. These diseases vary from simple steatosis to NASH, fibrosis, and cirrhosis. Most patients with NAFLD experience long-term diabetes or glucose-impaired tolerance . Type 2 diabetes mellitus is the most common type of diabetes. It has been that the highest percentage of NAFLD is present among obese patients with T2DM; approximately 75% of type 2 diabetic patients were diagnosed with NAFLD, especially NASH, and regularly exhibited more severe prognosis. A clear association between DM and NASH has been confirmed. DM has a vital role in enhancing liver injury progression, which consequently exaggerates abnormal glucose and lipid metabolism. As a result, the possible risks of cardiac-cerebral, vascular, and peripheral vascular events in DM patients are increased .Thus, avoiding liver injury is a vital issue during the management of DM. Studies also revealed the potential role of SGLT2 inhibitors, a kind of novel oral hypoglycemic agents, in improving dyslipidemia, liver steatosis and NASH . Therefore, the current study was conducted to investigate the efficacy of dapagliflozin to inhibit steatohepatitis in diabetic rats and examine the underlying mechanisms for this effect by assessment of the possible antioxidant and anti-inflammatory role of dapagliflozin along with its impact on TGFβ and alpha-SMA. Summary and conclusion 78 Methods and results : 1. Fifty rats weighing 120-150 gm were randomly distributed into five groups, ten rats each, and the rats were treated as follows. group 1: normal group and was fed by normal chow diet for 15 weeks. Starting from week 9, rats received saline. group 2: served as control diabetic and received saline. group 3, 4, and 5: received daily graded doses of dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.), respectively. All rats’ groups except group 1 were fed High Fat Diet (HFD) (10% lard, 2% cholesterol, 0.3% bile) for 8 weeks, followed by a single dose of STZ (30 mg/kg I.P) for diabetes mellitus induction. For additional 6 weeks, HFD was given along with the following treatment regimen. 2. Serum samples were collected and used for subsequent biochemical determination of liver enzymes, total cholesterol, triglycerides, serum insulin, and insulin resistance index. Rats were then sacrificed by cervical dislocation, and the liver tissues were dissected. Specimens of livers from different groups were intended for histopathological assessment. The rest of the liver tissues were frozen immediately at - 80ºC for homogenization and assessment of various biochemical parameters. 3. Assessment of NF-κB using western blot technique accompanied with SDS PAGE electrophoresis. ELISA was used to assess IL-1β, TGF- β beside determination of lipid peroxidation in the liver, such as Malondialdehyde (MDA), as well as oxidative stress indicators by measuring reduced glutathione (GSH) levels, catalase, and superoxide dismutase (SOD) activities. 4. The histological examination was performed using the histological scoring system for NAFLD by an experienced pathologist without prior Summary and conclusion 79 knowledge of the treatments. Evaluation of steatosis, steatohepatitis, and fibrosis based on Kleiner and Matsuzawa scoring system. 5. The hepatic steatosis induction was confirmed by an increase in total cholesterol and triglyceride levels compared to normal values along with the presence of marked hepatic steatosis by histological examination in addition to a significant increase in liver weight and liver index in diabetic control compared to the normal group (P<0.05). 6. Dapagliflozin treatment led to a significant (P<0.05) decrease in the liver index and significantly (P<0.05) depressed the level of total cholesterol and triglycerides compared to the control diabetic group. 7. The study results revealed high transaminase liver enzymes level in control diabetic group compared to the normal. Also, dapagliflozin has a noticeable hepatoprotective effect regarding controlling AST and ALT levels. This effect is due to the improvement of the metabolic balance mediated by SGLT2 inhibitors. 8. The results showed significant elevation of MDA level along with a reduction in GSH, SOD, and catalase levels in the control diabetic group, it also revealed the hepatoprotective effects of dapagliflozin by displaying a dose-dependent increase in the antioxidant enzymes SOD, Catalase activities, and GSH accompanied by decrease in MDA level. 9. The current study showed a clear inflammatory state in steatohepatitis, as evidenced by significant elevation in hepatic NF-κB and IL-1β levels in the control diabetic group. The potent hepatoprotective effect of dapagliflozin showed improving hyperglycemia-induced tissue inflammation mediated by diminishing NF-κB expression and IL-1β level. |