Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most frequent histological finding in individuals with abnormal liver-function tests in the Western countries. In previous studies, we have shown that oxidative phosphorylation (OXPHOS) is decreased in individuals with NAFLD, but the cause of this mitochondrial dysfunction remains uncertain. The aims of this study were to determine whether feeding mice a high-fat diet (HFD) induces any change in the activity of OXPHOS, and to investigate the mechanisms involved in the pathogenesis of this defect. To that end, 30 mice were distributed between five groups: control mice fed a standard diet, and mice on a HFD and treated with saline solution, melatonin (an antioxidant), MnTBAP (a superoxide dismutase analog) or uric acid (a scavenger of peroxynitrite) for 28 weeks intraperitoneously. In the liver of these mice, we studied histology, activity and assembly of OXPHOS complexes, levels of subunits of these complexes, gene expression of these subunits, oxidative and nitrosative stress, and oxidative DNA damage. In HFD-fed mice, we found nonalcoholic steatohepatitis, increased gene expression of TNFα, IFNγ, MCP-1, caspase-3, TGFβ1 and collagen α1(I), and increased levels of 3-tyrosine nitrated proteins. The activity and assembly of all OXPHOS complexes was decreased to about 50–60%. The amount of all studied OXPHOS subunits was markedly decreased, particularly the mitochondrial-DNA-encoded subunits. Gene expression of mitochondrial-DNA-encoded subunits was decreased to about 60% of control. There was oxidative damage to mitochondrial DNA but not to genomic DNA. Treatment of HFD-fed mice with melatonin, MnTBAP or uric acid prevented all changes observed in untreated HFD-fed mice. We conclude that a HFD decreased OXPHOS enzymatic activity owing to a decreased amount of fully assembled complexes caused by a reduced synthesis of their subunits. Antioxidants and antiperoxynitrites prevented all of these changes, suggesting that nitro-oxidative stress played a key role in the pathogenesis of these alterations. Treatment with these agents might prevent the development of NAFLD in humans.
Highlights
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases that occur in individuals who do not consume a significant amount of alcohol, extending from pure fatty liver through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocarcinoma (Matteoni et al, 1999)
Implications and future directions This study demonstrates that a high-fat diet (HFD) reduces oxidative phosphorylation (OXPHOS) enzymatic activity by decreasing the amount of fully assembled complexes, and that this defect is caused by reduced synthesis of their subunits
Further studies should better investigate these mechanisms and, in particular, address whether: (1) fatty acids are involved in the pathogenesis of this effect of HFD, (2) increased degradation of OXPHOS subunits might contribute to reduced OXPHOS activity, (3) NADPH oxidase is responsible for the HFD-induced nitrooxidative stress, (4) inhibition of NADPH oxidase prevents OXPHOS dysfunction and nonalcoholic steatohepatitis, and (5) fatty acids are able to activate this oxidase
Summary
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases that occur in individuals who do not consume a significant amount of alcohol, extending from pure fatty liver through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocarcinoma (Matteoni et al, 1999). Likewise, saturated FFAs increase superoxide anion production (Lambertucci et al, 2012) The combination of both superoxide and nitric oxide leads to the formation of peroxynitrite (Pryor and Squadrito, 1995), which can nitrate tyrosine residues within mitochondrial proteins and cause degradation of mitochondrial complexes and the loss of OXPHOS activity (Murray et al, 2003; García-Ruiz et al, 2010). This is the last step in a vicious circle that could progressively worsen the mitochondrial function. Mice fed a high-fat diet (HFD) are considered a valuable tool for investigating NAFLD (Ito et al, 2007)
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