Comparative study of obeticholic acid and rosuvastatin in high-fat/fructose diet-induced metabolic dysfunction: role of AMPK, PPAR-γ, SREBP-1c, and STAT3 pathways.

Metabolic syndrome (MetS), often modeled by high-fat/fructose (HFF) diets, involves dyslipidemia, hypertension, insulin resistance, and liver dysfunction. While Rosuvastatin (ROSU) effectively manages dyslipidemia, its potential diabetogenic effects raise concerns. Obeticholic acid (OCA), an FXR agonist, offers metabolic benefits but requires direct comparison with ROSU in this context. This study aimed to assess and compare the effect of Obeticholic acid vs Rosuvastatin in a rat model of high-fat/fructose diet-induced metabolic dysfunction, assessing biochemical, histological, and molecular endpoints relevant to dyslipidemia, insulin resistance, hemodynamics, and hepatic and adipose tissue injury. 27 Adult male albino rats were divided into four groups (each group seven rats): group 1: normal control, group 2: high-fat/fructose (HFF) diet (25% fat, 10% fructose) for 8 weeks, group 3: HFF + Rosuvastatin (10 mg/kg/day orally), and group 4: HFF + Obeticholic acid (10 mg/kg/day orally). Treatments were administered orally from 5th week. The study assessed lipid profiles, atherogenic indices, glucose metabolism parameters (fasting glucose, insulin, HOMA-IR), blood pressure, liver function marker (ALT), and hepatic gene expression (AMPK, SREBP1-c, PPAR-γ). In addition to Liver and adipose tissue histopathology, area percentage of collagen fibers, adipocytes diameter, PPAR-γ, STAT3 and PCNA immunoexpression. ROSU demonstrated superior efficacy in lowering total cholesterol, LDL-C, triglycerides, and atherogenic indices compared to OCA. However, ROSU significantly increased insulin levels and insulin resistance, highlighting its diabetogenic potential. Conversely, OCA exhibited a more pronounced beneficial effect on lowering both systolic and diastolic blood pressure compared to ROSU. Crucially, OCA did not exacerbate insulin levels or resistance relative to the HFF control group. Both treatments comparably reduced elevated ALT levels and improved hepatic histology in the context of HFF diet-induced pathology, which was associated with upregulated PPAR-γ and STAT3 immunoexpression. Both ROSU and OCA reversed these alterations and normalized cellular proliferation, as evidenced by PCNA immunoexpression in liver and adipose tissues. Additionally, they beneficially modulated hepatic gene expression by upregulating AMPK and downregulating the lipogenic factors SREBP-1c and PPAR-γ. In conclusion, OCA represents an alternative antihyperlipidemic, particularly when blood pressure control is a priority or to avoid Rosuvastatin’s diabetogenic side effects. Given their comparable efficacy in improving liver dysfunction.