Ketogenic Diet Attenuates Hepatopathy in Mouse Model of Respiratory Chain Complex III Deficiency

Carbohydrate-restricted high-fat ketogenic diets (KD) stimulate mitochondrial β-oxidation and ketone body production in the liver. Ketone bodies can be utilized as an alternative energy source by the brain, heart and skeletal muscle. KD is an established therapy in drug-resistant epilepsies, and has been proposed and tested as a therapy for mitochondrial disorders as well. For example, the group of Anu Suomalainen showed that in a mouse model of late-onset mitochondrial myopathy, KD decreased muscle fiber defects and mitochondrial ultrastructural abnormalities. In a subsequent study on myopathy patients, Atkins diet caused muscle pain and selective lysis of abnormal muscle fibers, which was considered eventually beneficial for the muscle function.

With the hypothesis that KD may induce mitochondrial biogenesis to compensate respiratory chain function and ameliorate disease progression, the Group Fellman performed a dietary intervention to assess the effect of KD on liver disease in the Bcs1l mutant mouse model of GRACILE syndrome, a neonatal mitochondrial disorder first described by Vineta Fellman.

The mutant mice became persistently ketotic on KD and their liver disease progression was attenuated as shown by delayed fibrosis, reduced cell death, inhibition of hepatic progenitor cell response and stellate cell activation, and normalization of liver enzyme activities. Complex III assembly and activity were improved and mitochondrial morphology in hepatocytes normalized. Histological findings and transcriptome changes indicated modulation of liver macrophagepopulations by the mutation and the diet.

These results revealed a striking beneficial hepatic response to KD in mice with mitochondrial hepatopathy, which warrants further investigations of dietary modification in the management of these conditions in patients.



Original Study:
Purhonen J, Rajendran J, Mörgelin M, Uusi-Rauva K, Katayama S, Krjutskov K, Einarsdottir E, Velagapudi V, Kere J, Jauhiainen M, Fellman V, Kallijärvi J. Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation. Sci Rep 7(1): 957, 2017