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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 10
[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
Total Affiliations: 3
Document type: Journal article
Source: Free Radical Biology and Medicine; v. 113, p. 190-202, DEC 2017.
Web of Science Citations: 12

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)

FAPESP's process: 14/02819-0 - Investigation of glucose and lipid metabolism alterations in a model of nicotinamide nucleotide transhydrogenase mitochondrial (NNT)deficiency .
Grantee:Juliana Cristine Rovani Rodrigues
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
Grantee:Aníbal Eugênio Vercesi
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
Grantee:Licio Augusto Velloso
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 15/22063-0 - Antioxidant Role of the Nicotinamide Nucleotide Transhydrogenase (NNT) in the Central Nervous System - Morphofunctional characterization in control mice and spontaneously Nnt gene mutant mice.
Grantee:Annelise Francisco
Support type: Scholarships in Brazil - Doctorate