Effects of PPARα, PPARγ, and dual PPARα/γ agonists on liver tissue and biochemical markers in NAFLD-induced Wistar rats

Background and purpose: Non-alcoholic fatty liver disease (NAFLD) is the most common liver-related metabolic disorder worldwide, affecting approximately 25% of the global population. Peroxisome proliferator-activated receptor (PPAR) agonists play an important role in NAFLD management through modulation of lipid metabolism and insulin sensitivity. This study compared the effects of fenofibrate (PPARα agonist), pioglitazone (PPARγ agonist), and saroglitazar (dual PPARα/γ agonist) in a high-fat diet (HFD)-induced NAFLD rat model. Experimental approach: NAFLD was induced in Wistar rats by feeding a high-fat diet. Animals were assigned to control, HFD, and HFD-treated groups receiving saroglitazar (3 mg/kg), pioglitazone (30 mg/kg), or fenofibrate (100 mg/kg) for six weeks. Anthropometric parameters, serum liver enzymes, lipid profile, fasting blood glucose, and HOMA-IR were assessed. Histopathological changes were evaluated using H&E and Masson’s trichrome staining. Hepatic expression of FGF21, CPT-1, PPARa, SREBP-1c, and ACC was analyzed by quantitative RT-PCR. Findings/Results: All three PPAR agonists significantly improved hepatic steatosis, inflammation, and fibrosis compared with the HFD group, despite variability in biochemical and metabolic parameters. Among the treatments, saroglitazar demonstrated the most pronounced histological improvement, although systemic metabolic improvements were comparable among all three agents. Conclusion and implications: Fenofibrate, pioglitazone, and saroglitazar exert beneficial effects on NAFLD progression through partially distinct mechanisms. Dual PPARα/γ activation appears to preferentially enhance hepatic histological outcomes, supporting the therapeutic relevance of saroglitazar in NAFLD.