The Effect of Liraglutide on the Hypolipidemic, Anti-Inflammatory, and Antioxidant Properties of Atorvastatin Mediated via the Nrf2/HO-1 Signaling Pathway: In Vivo and In Silico Validation

Introduction: Oxidative stress and inflammation are major factors linked to obesity and metabolic dysfunction, leading to a significantly higher risk of related diseases. Atorvastatin and liraglutide possess lipid-lowering, antioxidant, and anti-inflammatory effects that could synergistically improve obesity-related perturbations through modulation of the Nrf2/HO-1 signaling pathway. Methodology: We assessed liraglutide’s pharmacological potential in extending atorvastatin’s benefit on obesity, hyperlipidemia, and fatty liver in rats fed a high-fat diet (HFD) for 12 weeks. We specifically evaluated the effects of liraglutide treatment on atorvastatin-induced anti-inflammatory and antioxidant mechanisms, with a particular focus on Nrf2/HO 1 modulation in adipose and hepatic tissue. In silico analyses, including molecular docking and AlphaFold- Multimer modeling, evaluated the binding affinities of atorvastatin and liraglutide to Nrf2 and HO 1. Results: Compared to ND, the HFD-fed rats had a significantly higher final body weight (362.4 ± 12.7 g vs. 245.6 ± 9.8 g in ND, p < 0.05). There was a marked increase in serum total cholesterol (178.6 ± 9.2 mg/dL vs. 98.3 ± 6.4), fasting glucose (340.1 ± 8.2 mg/dL vs. 82.3 ± 3.1), HbA1c (7.8 ± 0.3 vs. 4.5 ± 0.2), and hepatic COX-2 expression (99.9 ± 6.3 vs 19.6 ± 2.4). The oxidative stress markers were also disturbed, as indicated by SOD (42.5 ± 3.1 vs. 95.2 ± 4.6 U/mg protein), GSH (18.3 ± 1.5 vs. 42.7 ± 2.8 nmol/mg), and p62 (0.005 ± 0.001 vs. 0.125 ± 0.01). Atorvastatin lowered cholesterol (121.2 ± 7.5 mg/dL), COX-2 (61.3 ± 3.3), and body weight (301.7 ± 11.5 g) compared to HFD. Meanwhile, liraglutide caused a greater reduction in body weight (268.5 ± 10.3 g), glucose (112.5 ± 6.7 mg/dL), and COX-2 (42.2 ± 2.9) than atorvastatin. The combination therapy produced the most significant effects, returning body weight (253.6 ± 9.1 g) to baseline, normalizing glucose and lipids, reducing COX-2 to 22.9 ± 2.0, and reactivating the Nrf2/HO-1 pathway, as shown by increased HO-1 expression and the restoration of p62 levels (0.078 ± 0.004). In silico analyses suggest that atorvastatin favorably binds to Nrf2 and HO-1, while liraglutide interacts with structurally relevant interfaces on these proteins, providing a mechanistic basis for their complementary antioxidant and cytoprotective effects. Conclusions: Our findings support targeting the Nrf2/HO-1 signaling pathway as a potential therapy for reversing hyperlipidemia and preventing mediators of inflammation and oxidative stress damage in the liver tissue. The evidence of increased efficacy observed with the combined atorvastatin and liraglutide supports a potential novel understanding of the complementary effects of atorvastatin and liraglutide. This finding requires further investigation to elucidate the combination’s therapeutic advantages in treating metabolic disorder scenarios.