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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Navarro, Claudia D. C. [1] ; Figueira, Tiago R. [1] ; Francisco, Annelise [1] ; Dal'Bo, Genoefa A. [1] ; Ronchi, Juliana A. [1] ; Rovani, Juliana C. [2] ; Escanhoela, Cecilia A. F. [3] ; Oliveira, Helena C. F. [2] ; Castilho, Roger F. [1] ; Vercesi, Anibal E. [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Patol Clin, BR-13083887 Campinas, SP - Brazil
[2] Univ Estadual Campinas UNICAMP, Inst Biol, Dept Biol Estrut & Func, BR-13083865 Campinas, SP - Brazil
[3] Univ Estadual Campinas UNICAMP, Fac Ciencias Med, Dept Anat Patol, BR-13083887 Campinas, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Free Radical Biology and Medicine; v. 113, p. 190-202, DEC 2017.
Citações Web of Science: 10
Resumo

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. (AU)

Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
Beneficiário:Licio Augusto Velloso
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 11/50400-0 - Metabolismo energético, estado redox e funcionalidade mitocondrial na morte celular e em desordens cardiometabólicas e neurodegenerativas
Beneficiário:Aníbal Eugênio Vercesi
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 15/22063-0 - Papel antioxidante da transidrogenase de nucleotídeos de nicotinamida (NNT) no sistema nervoso central - caracterização morfofuncional em camundongos controles e espontaneamente mutantes para o gene NNT
Beneficiário:Annelise Francisco
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 14/02819-0 - Estudo das alterações do metabolismo glicídico e lipídico em modelo com deficiência da transidrogenase de nucleotídeo de nicotinamida mitocondrial (NNT)
Beneficiário:Juliana Cristine Rovani Rodrigues
Linha de fomento: Bolsas no Brasil - Doutorado