Potential Effects of Naringenin on Hepatic Lipid Accumulation and Lipogenesis-Related Gene Expression in High-Fat Diet-Fed Rats

This study investigated the protective effects of naringenin (NAR) against metabolic dysfunction-associated steatotic liver disease (MASLD) in male Wistar rats fed a high-fat diet (HFD). We fed rats a high-fat diet for a total of 12 weeks, with oral NAR administered daily from weeks 9–12 (n = 8 rats/group). The HFD group (from week 9) were divided into four experimental groups: HFD (control); HFD+ 50 mg/kg NAR; HFD+ 100 mg/kg NAR; and HFD+ 200 mg/kg NAR. In addition, rats receiving standard diet (from week 9) were divided into two groups: a normal control (NC) group (i.e., standard diet + vehicle) and an NC+ 200 mg/kg NAR. NAR was orally administered for the last 4 weeks. We observed that the increasing doses (100 and 200 mg/kg) of NAR decreased body mass index (BMI), liver function markers, fasting plasma glucose and insulin, and HOMA-IR, and improved hepatic and serum lipid profiles. At 200 mg/kg, NAR reduced body weight by about 20.4%, BMI by 19.2%, serum ALT by 24%, AST by 43%, fasting glucose by 21%, fasting insulin by 44%, HOMA-IR by 56%, serum TG by 37%, TC by 41%, and LDL-c by 25%, and it increased HDL-c by 20%, relative to the HFD group. Similarly, it lowered the hepatic TG by 35.1%, TC by 28.4%, and LDL-C by 30.3%, while raising HDL-C by 31.8%. Histopathological examination of the liver revealed enhanced hepatocellular structure, reduced cytoplasmic vacuolation, decreased immune cell infiltration, and reduced injury scores. Furthermore, NAR was associated with improved antioxidant status, demonstrated by increasing the levels antioxidant mediators such as mRNA Nrf2, GSH, GSH-Px, SOD, and CAT in the liver. Moreover, it suppressed inflammatory mediators, including TNF-α, IL-1β, IL-6, and mRNA NF-κB, while elevating the anti-inflammatory cytokine IL-10. NAR was associated with increased hepatic SIRT1 and decreased PPARγ, ChREBP, and SREBP-1c mRNA levels. The more pronounced effect of NAR was observed at 200 mg/kg. These results of our study suggest the potential of NAR as a therapeutic candidate for MASLD, improving metabolic parameters and reducing hepatic lipid accumulation and inflammation associated with MASLD- like model, alongside improved antioxidant status and changes in SIRT1 and ChREBP/SREBP-1c expression.