Metformin plus naringin: a new optional treatment for metabolic dysfunction associated with fatty liver disease in a rat experimental model of high-fructose consumption.

Abstract

BACKGROUND: High-fructose diet (HFD) is recognized as a major dietary factor contributing to metabolic and hepatic alterations. The aim of this study was to determine whether the combined treatment with Metformin (Met) plus naringin (NAR) reverses the alterations that lead to metabolic dysfunction-associated fatty liver disease (MAFLD) in HFD-fed animals. MATERIALS AND METHODS: Male Wistar rats were divided in: 1) Control; 2) HFD: 10% fructose-rich drinking water for 60 days; 3) Met: HFD rats treated with Met (100 mg/kg b.w.); 4) NAR: HFD rats treated with NAR (40 mg/kg b.w); 5): Met + NAR. Met and/or NAR treatments began on the 21st day of fructose administration and concluded on day 60. Biochemical parameters were measured in serum, while liver samples were used for histological analysis, lipid profile assessment, evaluation of oxidative/nitrosative stress markers, inflammatory status, and apoptosis. RESULTS: HFD rats showed increased body weight, waist circumference, hepatosomatic index, adiposity, dyslipidemia, and elevated hepatic enzymes. Histological analyses revealed steatosis, fibrosis and hepatocyte ballooning. HFD also induced upregulation of ACC, SCD1, IL-6, and COX-2, and downregulation of PPARα and IL-10. Oxidative stress was shown by depletion of glutathione, elevated catalase and malondialdehyde, increased ROS, and higher apoptosis in hepatocytes. Met or NAR alone partially improved these alterations, while the combined treatment normalized most parameters, restoring liver morphology, reducing fibrosis and inflammation, suppressing lipogenesis, and enhancing antioxidant defenses. CONCLUSION: Combined Met + NAR improves systemic, structural, and molecular alterations in experimental MAFLD. These findings support its potential as a therapeutic strategy against HFD-related fatty liver disease.