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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Free Radical Biology and Medicine; v. 113, p. 190-202, DEC 2017.
• Web of Science Citations: 12

Abstract

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: 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: 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: 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: 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