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By CAFMI AI From Nutrition & Diabetes (Open Access)
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition characterized by excessive fat accumulation in the liver, linked closely to metabolic syndrome and mitochondrial dysfunction. The ketogenic diet (KD), which is low in carbohydrates and high in fats, has gained attention for its potential to modify metabolic pathways that contribute to MASLD pathogenesis. A recent study investigated the impact of KD on mitochondrial dynamics—specifically the balance between mitochondrial fission and fusion—and how this might ameliorate MASLD. Researchers used animal models with diet-induced MASLD to closely examine mitochondrial morphology, including structural integrity and functional protein expression such as dynamin-related protein 1 (Drp1) which promotes fission, and mitofusin 2 (Mfn2) which promotes fusion. Results showed that KD corrected the imbalance caused by MASLD by normalizing levels of Drp1 and Mfn2, restoring healthy mitochondrial morphology as confirmed by electron microscopy. This normalization of mitochondrial dynamics was associated with a significant improvement in mitochondrial respiratory function and a reduction in reactive oxygen species (ROS), which are harmful molecules that contribute to oxidative stress and liver injury. In addition to these cellular improvements, the KD also led to observable clinical benefits in these models, including less liver steatosis (fat accumulation) and decreased inflammation as supported by histological analysis. These findings highlight that KD acts not just on metabolic fat handling but crucially on mitochondrial quality control mechanisms, directly reversing pathological changes at the cellular energy production level.
MASLD management currently faces limited pharmacological options, making lifestyle and dietary interventions primary treatment modalities. This study’s findings position the ketogenic diet as a promising strategy to directly target mitochondrial dysfunction—a key contributor to disease progression in MASLD. Improved mitochondrial bioenergetics, demonstrated by enhanced fatty acid oxidation and increased ATP synthesis under KD treatment, suggests that this diet supports the liver’s energy metabolism more efficiently, reducing excess lipid deposits that characterize MASLD. For clinicians in the United States and elsewhere, these results are particularly pertinent given the high prevalence of metabolic syndrome and MASLD in primary care settings. The ability of KD to reduce oxidative stress and inflammation further underscores its therapeutic potential in interrupting progression to more severe liver diseases such as steatohepatitis or fibrosis. However, practical implementation requires careful patient selection and monitoring, as ketogenic diets demand adherence to strict macronutrient ratios and may not be suitable for all patients, especially those with contraindications like certain metabolic disorders or kidney disease. Given the complex relationship between mitochondrial health and overall metabolic function, KD could be integrated as part of a comprehensive care plan involving nutritional counseling, monitoring of liver enzymes and metabolic markers, and longitudinal follow-up to assess liver function improvement and dietary compliance.
While animal model data are compelling, translation into clinical practice requires controlled trials to define the benefits, risks, and optimal protocols for KD in MASLD management.. These studies should focus on the appropriate duration, macronutrient composition, and target patient populations most likely to benefit. Additionally, clinicians should be aware of potential limitations and adverse effects of ketogenic diets including nutrient deficiencies, gastrointestinal symptoms, and possible impacts on lipid profiles that require monitoring. From a diagnostic and workflow standpoint, primary care providers should consider MASLD in patients presenting with metabolic syndrome features and unexplained elevated liver enzymes. Early counseling on dietary modification, including the potential role of KD, can be integrated into primary-care workflows. Such incorporation necessitates interdisciplinary collaboration, involving dietitians and hepatologists to tailor interventions for individual patient needs and comorbidities. Finally, patient education about red flags indicating liver disease progression—such as jaundice, abdominal pain, or unexplained weight loss—is vital for timely referral and management. Overall, the ketogenic diet offers a biologically plausible and promising avenue for MASLD treatment through mitochondrial function restoration, but its clinical adoption must be informed by ongoing research and patient-centered care strategies.
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