NEIL1 and Metabolic Syndrome

Background and Previous Work

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.

Most Recent Work

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.

Publications

Sampath H, McCullough AK, Lloyd RS. Regulation of DNA glycosylases and their role in limiting disease. Free Radic Res. 2012 Feb 6 [Epub ahead of print]. PMID: 22300253

Sampath H, Batra AK, Varatanian V, Carmical JR, Prusak D, King IB, Lowell B, Earley LF, Wood TG, Marks DL, McCullough AK, Lloyd RS.  Variable penetrance of metabolic phenotypes and development of high fat diet-induced adiposity in NEIL1-deficient mice. Am J Physiol Endocrinol Metab. 300(4): E724-E735, 2011 PMID: 21285402

Jaruga P, Xiao Y, Vartanian V, Lloyd RS, Dizdaroglu M. Evidence for the involvement of DNA repair enzyme NEIL1 in nucleotide excision repair of (5'R)- and (5'S)-8,5'-cyclo-2'-deoxyadenosines. Biochemistry. 49(6): 1053-5, 2010. PMID: 20067321  

Mori H, Ouchida R, Hijikata A, Kitamura H, Ohara O, Li Y, Gao X, Yasui A, Lloyd RS, Wang JY. Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion. DNA Repair (Amst). 8(11):1328-32, 2009. PMID: 19782007

Chan MK, Ocampo-Hafalla MT, Vartanian V, Juruga P, Kirkali G, Koenig KL, Brown S, Lloyd RS, Dizdaroglu M, Teebor GW. Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA. DNA Repair (Amst). 8(7):786-94, 2009. PMID: 19346169  

Roy LM, Jaruga P, Wood TG, McCullough AK, Dizdaroglu M, Lloyd RS. Human polymorphic variants of the NEIL1 DNA glycosylase. J Biol Chem. 282(21):15790-8, 2007. PMID: 17389588

Vartanian V, Lowell B, Minko IG, Wood TG, Ceci JD, George S, Ballinger SW, Corless CL, McCullough, AK, Lloyd RS. The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. Proc Natl Acad Sci U S A. 103(6):1864-9, 2006. PMID: 16446448