Comparative Efficacy of Pioglitazone, Saroglitazar, and Silymarin on Biochemical and Histopathological Hepatic Outcomes in a Wistar Rat Model of Non-alcoholic Fatty Liver Disease and Their Correlation With Insulin Sensitivity

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide and is strongly associated with metabolic syndrome. Comparative evaluation of commonly used pharmacological agents is limited. This study aimed to evaluate and compare the effects of pioglitazone (PPAR‑γ agonist), saroglitazar (dual PPAR‑α/γ agonist), and silymarin on biochemical, anthropometric, and histopathological outcomes in a high-fat diet (HFD) Wistar rat model of NAFLD, and to assess their impact on insulin sensitivity Material and methods: Thirty adult male Wistar rats were randomized into five groups (n=6 each): normal control (standard diet), NAFLD control (HFD), and three treatment groups receiving pioglitazone (10 mg/kg), saroglitazar (4 mg/kg), or silymarin (400 mg/kg) orally for 28 days after seven weeks of HFD administration. Outcomes assessed included body weight (BW) and liver weight (LW), serum lipid profile, alanine aminotransferase (ALT), fasting glucose, insulin, Homeostasis Model Assessment of Insulin Resistance (HOMA‑IR), and histopathological scoring (steatosis, inflammation, fibrosis). RESULTS: Saroglitazar consistently provided the greatest benefits, showing significant reduction in serum cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL‑c), very low-density lipoprotein cholesterol (VLDL‑c), ALT, and HOMA‑IR, with marked restoration of high-density lipoprotein cholesterol (HDL‑c) and improved histology. Pioglitazone was effective in improving insulin sensitivity and steatosis, while silymarin exhibited hepatoprotective effects but with relatively modest improvements. INTERPRETATION AND CONCLUSIONS: Saroglitazar demonstrated the most comprehensive protective effects against NAFLD progression, surpassing pioglitazone and silymarin in biochemical, histological, and insulin resistance parameters. Its dual PPAR‑α/γ activity may offer a more effective therapeutic approach, supporting further translational evaluation in NAFLD management.