8-Oxoguanine DNA Glycosylase OGG1 Deficiency Increases Susceptibility to Obesity and Metabolic DysfunctionReportar como inadecuado

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Oxidative damage to DNA is mainly repaired via base excision repair, a pathway that is catalyzed by DNA glycosylases such as 8-oxoguanine DNA glycosylase OGG1. While OGG1 has been implicated in maintaining genomic integrity and preventing tumorigenesis, we report a novel role for OGG1 in altering cellular and whole body energy homeostasis. OGG1-deficient Ogg1−-− mice have increased adiposity and hepatic steatosis following exposure to a high-fat diet HFD, compared to wild-type WT animals. Ogg1−-− animals also have higher plasma insulin levels and impaired glucose tolerance upon HFD feeding, relative to WT counterparts. Analysis of energy expenditure revealed that HFD-fed Ogg1−-− mice have a higher resting VCO2 and consequently, an increased respiratory quotient during the resting phase, indicating a preference for carbohydrate metabolism over fat oxidation in these mice. Additionally, microarray and quantitative PCR analyses revealed that key genes of fatty acid oxidation, including carnitine palmitoyl transferase-1, and the integral transcriptional co-activator Pgc-1α were significantly downregulated in Ogg1−-− livers. Multiple genes involved in TCA cycle metabolism were also significantly reduced in livers of Ogg1−-− mice. Furthermore, hepatic glycogen stores were diminished, and fasting plasma ketones were significantly reduced in Ogg1−-− mice. Collectively, these data indicate that OGG1 deficiency alters cellular substrate metabolism, favoring a fat sparing phenotype, that results in increased susceptibility to obesity and related pathologies in Ogg1−-− mice.

Autor: Harini Sampath, Vladimir Vartanian, M. Rick Rollins, Kunihiko Sakumi, Yusaku Nakabeppu , R. Stephen Lloyd

Fuente: http://plos.srce.hr/


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