| First Author | Navarro CDC | Year | 2017 |
| Journal | Free Radic Biol Med | Volume | 113 |
| Pages | 190-202 | PubMed ID | 28964917 |
| Mgi Jnum | J:319248 | Mgi Id | MGI:6863334 |
| Doi | 10.1016/j.freeradbiomed.2017.09.026 | Citation | Navarro CDC, et al. (2017) Redox imbalance due to the loss of mitochondrial NAD(P)-transhydrogenase markedly aggravates high fat diet-induced fatty liver disease in mice. Free Radic Biol Med 113:190-202 |
| abstractText | 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 Ca(2+)-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. |
