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 HO release rate from mitochondria, decreased aconitase activity (a redox-sensitive mitochondrial enzyme) and higher susceptibility to Ca-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.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1016/j.freeradbiomed.2017.09.026 | DOI Listing |
Antioxid Redox Signal
November 2024
Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands.
Horm Metab Res
October 2024
Department of Pathology, State University of Campinas (UNICAMP), Campinas, Brazil.
Commun Chem
October 2024
Inorganic & Organic Nanomedicine (ION) Lab, Institute of Nano Science and Technology, Sector 81, Knowledge City, Mohali, 140306, Punjab, India.
Acta Neuropathol Commun
May 2024
Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI, 48201, USA.
Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied.
View Article and Find Full Text PDFExp Gerontol
August 2024
Department of Pathology, School of Medical Sciences, University of Campinas (UNICAMP), 13083 887 Campinas, SP, Brazil. Electronic address:
Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P) transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt) mice and age-matched controls (Nnt), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!