Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation

• Published in: Scientific reports 2017-04, Vol.7 (1), p.957-16, Article 957
• Main Authors: Purhonen, Janne, Rajendran, Jayasimman, Mörgelin, Matthias, Uusi-Rauva, Kristiina, Katayama, Shintaro, Krjutskov, Kaarel, Einarsdottir, Elisabet, Velagapudi, Vidya, Kere, Juha, Jauhiainen, Matti, Fellman, Vineta, Kallijärvi, Jukka
• Format: Article
• Language: English
• Subjects: 13/1; 13/21; 13/51; 38/77; 38/90; 38/91; 631/443/319/1642; 64/60; 692/4020/4021/1607; 82/29; Animal models; Animals; ATPases Associated with Diverse Cellular Activities - genetics; Basic Medicine; Biosynthesis; Cell activation; Cell and Molecular Biology; Cell death; Cell- och molekylärbiologi; Cells, Cultured; Diet; Diet, Ketogenic; Disease Models, Animal; Electron transport; Electron Transport Complex III - deficiency; Electron Transport Complex III - genetics; Enzymatic activity; Evolution; Fibrosis; Gene expression; Glutathione transferase; Hepatic Stellate Cells - cytology; Hepatocytes; High carbohydrate diet; High fat diet; Humanities and Social Sciences; Humans; Inborn errors of metabolism; Ketogenesis; Liver; Liver diseases; Liver Diseases - diet therapy; Liver Diseases - etiology; Low carbohydrate diet; Low fat diet; Macrophages; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mice; Mitochondria; Mitochondrial Myopathies - complications; Mitochondrial Myopathies - genetics; multidisciplinary; Mutation; Nutrient deficiency; Progenitor cells; Rodents; Science; Science (multidisciplinary); Treatment Outcome
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-01109-4

Mitochondrial disorders are among the most prevalent inborn errors of metabolism but largely lack treatments and have poor outcomes. High-fat, low-carbohydrate ketogenic diets (KDs) have shown beneficial effects in mouse models of mitochondrial myopathies, with induction of mitochondrial biogenesis as the suggested main mechanism. We fed KD to mice with respiratory chain complex III (CIII) deficiency and progressive hepatopathy due to mutated BCS1L, a CIII assembly factor. The mutant mice became persistently ketotic and tolerated the KD for up to 11 weeks. Liver disease progression was attenuated by KD as shown by delayed fibrosis, reduced cell death, inhibition of hepatic progenitor cell response and stellate cell activation, and normalization of liver enzyme activities. Despite no clear signs of increased mitochondrial biogenesis in the liver, CIII assembly and activity were improved and mitochondrial morphology in hepatocytes normalized. Induction of hepatic glutathione transferase genes and elevated total glutathione level were normalized by KD. Histological findings and transcriptome changes indicated modulation of liver macrophage populations by the mutation and the diet. These results reveal a striking beneficial hepatic response to KD in mice with mitochondrial hepatopathy and warrant further investigations of dietary modification in the management of these conditions in patients.