Hepatic transcriptomic and functional responses to ketogenic diet intervention in MASLD-Induced male albino rats

This study aimed to evaluate the potential therapeutic effects of the ketogenic diet (KD) on metabolic dysfunction-associated steatotic liver disease (MASLD). Forty male albino rats were randomly assigned to four groups: a control group, a MASLD group fed a high-fructose high-fat diet (HFFD) for eight weeks, a KD group provided a diet consisting of 65% fat, 25% protein, and 5% carbohydrates for 16 weeks, and a MASLD + KD group subjected to HFFD followed by KD. The MASLD group exhibited significant increases in serum leptin (1.94 ± 0.54 ng/mL vs. 1.24 ± 0.23 ng/mL in controls), urea (42.3 ± 4.5 mg/dL vs. 26.92 ± 6.57 mg/dL in controls), creatinine (0.97 ± 0.8 mg/dL vs. 0.67 ± 0.1 mg/dL in controls), triglycerides (98.6 ± 18.5 mg/dL vs. 78.6 ± 9.2 mg/dL in controls), and LDL cholesterol (89.9 ± 12 mg/dL vs. 40.8 ± 4.9 mg/dL in controls), while adiponectin (1.98 ± 0.21 µg/mL vs. 4.58 ± 0.69 µg/mL in controls) and HDL (21.4 ± 3.5 mg/dL vs. 39.8 ± 5.2 mg/dL in controls) were markedly reduced. Gene expression analysis revealed that Growth Arrest Specific 5 (GAS5), Neurogenic Locus Notch Homolog Protein 1 (Notch-1), H19, peroxisome proliferator-activated receptor gamma (PPARγ), stearoyl-CoA desaturase-1 (SCD1), acetyl-CoA carboxylase-1 (ACC1), fatty acid synthase (FASN), Neat-1, miR-139-5p, c-Jun, sterol regulatory element-binding transcription factor-1c (SREBF1c), Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT-1), aryl hydrocarbon receptor nuclear translocator (ARNT-1), and CD36 were significantly (p < 0.0001) upregulated in the MASLD group compared with the other groups. In contrast, the KD group demonstrated notable upregulation of microRNAs (miR-29a-3p, miR-130a, miR-139-5p, miR-206) and peroxisome proliferator-activated receptor alpha (PPARα) compared with the MASLD and MASLD + KD groups. Overall, the KD group exhibited the most pronounced improvements in metabolic, renal, and molecular parameters. These findings suggest that KD intervention may confer beneficial effects on metabolic and genetic pathways in MASLD, although causality cannot be definitively established in this experimental model.