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

Purhonen, Janne; Rajendran, Jayasimman; Mörgelin, Matthias LU ; Uusi-Rauva, Kristiina; Katayama, Shintaro; Krjutskov, Kaarel; Einarsdottir, Elisabet; Velagapudi, Vidya; Kere, Juha and Jauhiainen, Matti, et al. (2017) In Scientific Reports 7(1).
Abstract

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... (More)

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.

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Scientific Reports
volume
7
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85018392865
  • wos:000399536300013
ISSN
2045-2322
DOI
10.1038/s41598-017-01109-4
language
English
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yes
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c04446ee-f37a-48f9-8d31-6fc166387aee
date added to LUP
2017-05-17 08:32:45
date last changed
2017-09-18 11:35:57
@article{c04446ee-f37a-48f9-8d31-6fc166387aee,
  abstract     = {<p>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.</p>},
  articleno    = {1109},
  author       = {Purhonen, Janne and Rajendran, Jayasimman and Mörgelin, Matthias and Uusi-Rauva, Kristiina and Katayama, Shintaro and Krjutskov, Kaarel and Einarsdottir, Elisabet and Velagapudi, Vidya and Kere, Juha and Jauhiainen, Matti and Fellman, Vineta and Kallijärvi, Jukka},
  issn         = {2045-2322},
  language     = {eng},
  month        = {04},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation},
  url          = {http://dx.doi.org/10.1038/s41598-017-01109-4},
  volume       = {7},
  year         = {2017},
}