Ketogenic diet ameliorates MASLD via balancing mitochondrial dynamics and improving mitochondrial dysfunction.

BACKGROUND & AIMS: Ketogenic diet (KD) is recognized as an effective lifestyle intervention for managing metabolic dysfunction-associated steatotic liver disease (MASLD). This research aimed to assess the impact of KD on metabolic parameters in MASLD mice and elucidate the underlying mechanism. METHODS: High-fat diet (HFD)-induced MASLD mice were subjected to KD for 2 weeks. Researchers measured hepatic fat, plasma Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST) levels to assess metabolic changes. Hepatic mitochondrial dynamics were examined using transmission electron microscopy and Western blot. Mitochondrial functions were evaluated through Quantitative Polymerase Chain Reaction (qPCR) and measurement of ATP content. In vitro, HepG2 cells were treated with palmitate (PA), β-hydroxybutyric acid (β-OHB), and/or the mitochondrial fusion inhibitor MFI8 to study mitochondrial morphology, function, and lipid deposition. RESULTS: KD feeding partially improved the MASLD phenotype and reduced Fission 1 protein (Fis1) and Dynamin-related protein 1 (Drp1) levels in the livers of MASLD mice. Additionally, KD ameliorated HFD-stimulated mitochondrial dysfunctions, as evidenced by elevated ATP levels and upregulation of key genes responsible for fatty-acid-oxidation. β-OHB mitigated PA-stimulated mitochondrial dysfunction and fission in HepG2 cells. Furthermore, β-OHB attenuated PA-stimulated lipid deposition, with this effect being counteracted by MFI8. CONCLUSIONS: Our study suggests that a 2-week KD partially alleviates lipid deposition, restores mitochondrial dynamics balance, and improves mitochondrial dysfunctions in the livers of MASLD mice.