NEIL1 and Metabolic Syndrome
A mouse model of Metabolic Syndrome has resulted from the knockout of the neil1 gene that encodes a DNA repair glycosylase involved in the initiation of DNA base excision repair (BER) at oxidatively damaged purines (Vartanian et al, 2006; Sampath et al, 2011). Disease manifestations in neil1-/- mice include mid-life onset of obesity, dyslipidemia/fatty liver disease, insulin resistance, and lung and liver cancers, with male neil1-/- mice more severely affected than female littermates. Relative to neil1+/+ mice, hepatic mitochondrial DNAs (mtDNA) from neil1-/- mice show increased steady-state levels of DNA base damage and deletions, and total DNA accumulates high levels of oxidatively-damaged purine bases. Physiological profiling of 2 month old neil1-/- mice following a 6 week high-fat diet (HFD), demonstrated greater total weight and fat mass gains, more severe fatty liver disease, increased mtDNA damage, and significant modulation in gene expression relative to neil1+/+ littermates.
Since it is known that excessive oxidative stress conditions can trigger Metabolic Syndrome in wild-type animals, it is hypothesized that the loss of repair of oxidative DNA lesions lowers the threshold for the amount of oxidative stress that is required to induce these diseases. Overwhelming the DNA repair capacity within the cell leads to diminished and aborted mtDNA replication and transcription, thus compromising energy production and disrupting metabolic homeostasis. In support of this proposal, mice deficient in another DNA glycosylase (OGG1) also display a male-dominated obesity and fatty liver phenotype, very similar to the neil1-/- mice. Data derived from these two mouse models clearly demonstrate that interference with DNA repair of oxidative lesions can lead to symptoms of Metabolic Syndrome. Alternative outcomes, such as the cancers observed in the neil1-/- mice, are likely due to the accumulation of unrepaired base damage in nuclear DNAs and mutations arising from replication of these sites. In order to test this hypothesis concerning the molecular basis for the onset of symptoms of the Metabolic Syndrome, investigations are in progress to test the hypothesis that the progression of physiological changes in oxidatively-stressed, DNA repair-deficient mice and cells derived from them, can be correlated with the accumulation of mtDNA deletions and base damage, using a variety of pro-oxidant challenges. Extensive physiological profiling will be carried out. In addition to the mouse colonies described above, transgenic mice carrying the wild-type human neil1 (hneil1) gene or a catalytically-inactive polymorphic variant of hneil1 will be evaluated.
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