Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice

Autor: Juliana C. Rovani, Tiago R. Figueira, Anibal E. Vercesi, Claudia D. C. Navarro, Cecília Amélia Fazzio Escanhoela, Annelise Francisco, Helena C. F. Oliveira, Roger F. Castilho, Genoefa A. Dal'Bó, Juliana A. Ronchi
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Antioxidant
medicine.medical_treatment
Mitochondria
Liver
Pyruvate Dehydrogenase Complex
Mitochondrion
Biology
Diet
High-Fat
Biochemistry
NADP Transhydrogenase
AB-Specific
Mitochondrial Proteins
Mice
03 medical and health sciences
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
health services administration
Physiology (medical)
Internal medicine
medicine
Animals
Phosphorylation
Triglycerides
Aconitate Hydratase
Mice
Knockout
digestive
oral
and skin physiology
Fatty liver
food and beverages
nutritional and metabolic diseases
Hydrogen Peroxide
medicine.disease
Pyruvate dehydrogenase complex
Mice
Inbred C57BL
Disease Models
Animal
Oxidative Stress
030104 developmental biology
Endocrinology
Mitochondrial permeability transition pore
Mutation
NAD+ kinase
Steatohepatitis
Protein Processing
Post-Translational
030217 neurology & neurosurgery
Zdroj: Free Radical Biology and Medicine. 113:190-202
ISSN: 0891-5849
Popis: The mechanisms by which a high fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunctions and redox imbalance. We hypothesized that a HFD would increase mitochondrial reliance on NAD(P)-transhydrogenase (NNT) as the source of NADPH for antioxidant systems that counteract NAFLD development. Therefore, we studied HFD-induced liver mitochondrial dysfunctions and NAFLD in C57Unib.B6 congenic mice with (Nnt+/+) or without (Nnt-/-) NNT activity; the spontaneously mutated allele (Nnt-/-) was inherited from the C57BL/6J mouse substrain. After 20 weeks on a HFD, Nnt-/- mice exhibited a higher prevalence of steatohepatitis and content of liver triglycerides compared to Nnt+/+ mice on an identical diet. Under a HFD, the aggravated NAFLD phenotype in the Nnt-/- mice was accompanied by an increased H2O2 release rate from mitochondria, decreased aconitase activity (a redox-sensitive mitochondrial enzyme) and higher susceptibility to Ca2+-induced mitochondrial permeability transition. In addition, HFD led to the phosphorylation (inhibition) of pyruvate dehydrogenase (PDH) and markedly reduced the ability of liver mitochondria to remove peroxide in Nnt-/- mice. Bypass or pharmacological reactivation of PDH by dichloroacetate restored the peroxide removal capability of mitochondria from Nnt-/- mice on a HFD. Noteworthy, compared to mice that were chow-fed, the HFD did not impair peroxide removal nor elicit redox imbalance in mitochondria from Nnt+/+ mice. Therefore, HFD interacted with Nnt mutation to generate PDH inhibition and further suppression of peroxide removal. We conclude that NNT plays a critical role in counteracting mitochondrial redox imbalance, PDH inhibition and advancement of NAFLD in mice fed a HFD. The present study provide seminal experimental evidence that redox imbalance in liver mitochondria potentiates the progression from simple steatosis to steatohepatitis following a HFD.
Databáze: OpenAIRE
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