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

Publication date: December 2017
Source:Free Radical Biology and Medicine, Volume 113
Author(s): Claudia D.C. Navarro, Tiago R. Figueira, Annelise Francisco, Genoefa A. Dal'Bó, Juliana A. Ronchi, Juliana C. Rovani, Cecilia A.F. Escanhoela, Helena C.F. Oliveira, Roger F. Castilho, Anibal E. Vercesi
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.

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