The impact of medium chain triglyceride ketogenic diet on liver mitochondria and cytochrome P450 2E1

The ketogenic diet is increasingly used for metabolic and neurologic indications, yet its impact on hepatic mitochondrial function and xenobiotic metabolism remains incompletely defined. Cytochrome P450 2E1 (CYP2E1) is induced by the ketone body acetone and contributes to oxidative and carbonyl stress, but prior studies examining CYP2E1 regulation during ketosis have yielded conflicting results. Here, we investigated the effects of an 8-week medium chain triglyceride ketogenic diet (MCT-KD) on liver mitochondrial respiratory chain activity and CYP2E1 expression in young and aged Fisher 344 × Brown Norway F1 rats. In young animals, MCT-KD significantly reduced mitochondrial complex I activity without significant changes in complexes II, III, or IV. These changes occurred without altered citrate synthase activity, suggesting comparable mitochondrial content. In parallel, MCT-KD robustly increased hepatic CYP2E1 protein levels and activity in young and aged animals and upregulated its electron donor, P450 oxidoreductase (POR), particularly in young rats. Despite robust induction of the acetone-CYP2E1 pathway, methylglyoxal-derived protein adducts did not accumulate, even though hepatic GLO1 expression was reduced. Together, these findings demonstrate that long-term MCT-KD induces coordinated adaptations in hepatic mitochondrial function and the CYP2E1-POR pathway without increasing methylglyoxal-derived protein damage.