Abstract
The aim of this study was to evaluate the role of NADPH oxidase (NADPHox) in the pathogenesis of oxidative phosphorylation (OXPHOS) dysfunction as found in mice fed a high-fat diet (HFD). C57BL/6J mice were distributed in four groups: WT/SCD: six wild-type (WT) mice fed a standard chow diet (SCD); WT/HFD, six WT mice fed a HFD; NOX2−/−/SCD, six NADPHox-deficient mice on a SCD; (4) NOX2−/−/HFD, six NADPHox-deficient mice on a HFD. After 32 weeks, we studied the liver for: histology; OXPHOS complex activity; fully assembled OXPHOS complexes and their subunits; gene expression of OXPHOS subunits; oxidative and nitrosative stress; and oxidative DNA damage. In the liver of WT/HFD mice, we found a significant decreased in the activity of all OXPHOS complexes, in fully assembled complexes, in the amount of OXPHOS subunits, and in gene expression of mitochondrial DNA-encoded subunits. 8-hydroxy-2′-deoxyguanosine was only increased in mitochondrial DNA. The liver of NOX−/−/HFD mice showed mild steatosis but no non-alcoholic steatohepatitis (NASH) lesions were found. OXPHOS activity, OXPHOS subunits, and assembly of subunits into OXPHOS complexes were normal in these mice. We conclude that this study shows that NADPH deficiency protects mice from developing OXPHOS dysfunction and NASH caused by a HFD.
Highlights
That silencing XDH with appropriated small interfering RNAs did not prevent nitro-oxidative stress caused by saturated fatty acids in HepG2 cells[16]
Other authors have reported that steatosis development, lipid peroxidation, inflammation, and pericellular fibrosis caused by a methionine and choline-deficient (MCD) diet is independent of nicotinamide adenine dinucleotide phosphate-oxidase (NADPHox)[22], as the same histological lesions were observed in the liver of NADPHox-deficient and wild-type mice fed a MCD diet
Because NADPHox may play a major role in the pathogenesis of oxidative stress in non-alcoholic steatohepatitis (NASH), we fed NADPHox-deficient mice a high-fat diet (HFD) for 32 weeks
Summary
That silencing XDH with appropriated small interfering RNAs did not prevent nitro-oxidative stress caused by saturated fatty acids in HepG2 cells[16]. Other authors have reported that steatosis development, lipid peroxidation, inflammation, and pericellular fibrosis caused by a methionine and choline-deficient (MCD) diet is independent of NADPHox[22], as the same histological lesions were observed in the liver of NADPHox-deficient and wild-type mice fed a MCD diet This animal model of NASH has been criticised for not replicating the phenotype and pathogenic mechanism of human NASH. The aims of this study were to determine whether increased NADPHox activity in the liver is implicated in the pathogenesis of the nitro-oxidative stress found in mice on a HFD and to understand the role played by this enzyme complex in the dysfunction of OXPHOS in these mice
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