title: NADPH oxidase is implicated in the pathogenesis of oxidative phosphorylation dysfunction in mice fed a high-fat diet.
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.
authors.affiliation: Centro de Investigación, Laboratorio de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Universidad Complutense, 28041-Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: García-Ruiz
authors.affiliation: Institute of Liver Studies, King's College Hospital, SE5 9RS, London, United Kingdom.
authors.forename: Pablo
authors.initials: P
authors.lastname: Solís-Muñoz
authors.affiliation: Servicio de Bromatología e Higiene Alimentaria, Centro Militar de Veterinaria del Ministerio de Defensa, 28024-Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fernández-Moreira
authors.affiliation: Centro de Investigación, Laboratorio de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Universidad Complutense, 28041-Madrid, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Grau
authors.affiliation: Centro de Investigación, Laboratorio de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Universidad Complutense, 28041-Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Muñoz-Yagüe
authors.affiliation: Centro de Investigación, Laboratorio de Gastroenterología y Hepatología, Hospital Universitario 12 de Octubre, Universidad Complutense, 28041-Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Solís-Herruzo
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015870:Gene Expression; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003849:Deoxyguanosine; D000074662:NADPH Oxidase 2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse