Summary:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common metabolic condition characterised by excess fat accumulation in the liver and is closely linked to obesity, insulin resistance, dyslipidaemia, and hypertension. While pharmacological treatments have recently emerged, they can cause adverse effects, meaning lifestyle approaches such as diet and physical activity remain important. The ketogenic diet, characterised by very low carbohydrate intake, high fat intake, and moderate protein intake, results in a metabolic shift from glucose to fatty acids and ketone bodies as a primary energy source. Research has shown this diet can improve body weight, blood glucose, and lipid profiles, particularly in people with metabolic disease. Evidence also suggests that ketone bodies may reduce liver fat, inflammation, and fibrosis. However, the mechanisms to explain these effects are not fully understood. This experimental study aimed to determine whether a ketogenic diet could improve MASLD by improving mitochondrial performance. Mice with high-fat-diet-induced MASLD were fed a ketogenic diet for two weeks. Liver fat content, liver enzymes, mitochondrial structure, and markers of mitochondrial function were assessed. The findings showed that the ketogenic diet partially improved MASLD, increased ATP production, and upregulated genes involved in fatty acid oxidation. Ketones also reduced fat-induced mitochondrial dysfunction, excessive mitochondrial division, and lipid accumulation in liver cells. Overall, these findings indicate that short-term ketogenic diet intervention can partially reduce liver fat accumulation, rebalance mitochondrial dynamics, and improve mitochondrial function in MASLD.
Abstract:
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.
Article Publication Date: 25/08/2025
DOI: 10.1038/s41387-025-00391-w
