Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice.
Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial-derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle-aged mice. Susceptibility to diet-induced obesity increased with age. Young adult and middle-aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age-related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat-fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid-derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet-induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized.
Chair of Molecular Nutritional Medicine, Technische Universität München, Else Kröner Fresenius Center for Nutritional Medicine, Freising-Weihenstephan, Germany Z I E L - Research Center for Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany.
Kerstin
K
Lohr
Chair of Proteomics and Bioanalytics, Technische Universität München Bavarian Biomolecular Mass Spectrometry Center, Freising-Weihenstephan, Germany.
Fiona
F
Pachl
Chair of Proteomics and Bioanalytics, Technische Universität München Bavarian Biomolecular Mass Spectrometry Center, Freising-Weihenstephan, Germany.
Amin
A
Moghaddas Gholami
Z I E L - Research Center for Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany Nutritional Physiology, Technische Universität München, Freising-Weihenstephan, Germany.
Kerstin E
KE
Geillinger
Z I E L - Research Center for Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany Nutritional Physiology, Technische Universität München, Freising-Weihenstephan, Germany.
Hannelore
H
Daniel
Chair of Proteomics and Bioanalytics, Technische Universität München Bavarian Biomolecular Mass Spectrometry Center, Freising-Weihenstephan, Germany.
Bernhard
B
Kuster
Chair of Molecular Nutritional Medicine, Technische Universität München, Else Kröner Fresenius Center for Nutritional Medicine, Freising-Weihenstephan, Germany Z I E L - Research Center for Nutrition and Food Sciences, Technische Universität München, Freising-Weihenstephan, Germany mk@tum.de.
Martin
M
Klingenspor
D000367:Age Factors; D000818:Animals; D003430:Cross-Sectional Studies; D059305:Diet, High-Fat / Q000009:adverse effects*; D002149:Energy Intake / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology* / Q000662:veterinary; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D010084:Oxidation-Reduction; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism
D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases
Age; diet‐induced obesity; fatty acid oxidation; mitochondria; nonalcoholic fatty liver disease; proteomics
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