The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Vladimir Vartanian, Brian Lowell, Irina G. Minko, Thomas Wood, Jeffrey D. Ceci, Shakeeta George, Scott W. Ballinger, Christopher L. Corless, Amanda K. McCullough, R. Stephen Lloyd

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Endogenously formed reactive oxygen species continuously damage cellular constituents including DNA. These challenges, coupled with exogenous exposure to agents that generate reactive oxygen species, are both associated with normal aging processes and linked to cardiovascular disease, cancer, cataract formation, and fatty liver disease. Although not all of these diseases have been definitively shown to originate from mutations in nuclear DNA or mitochondrial DNA, repair of oxidized, saturated, and ring-fragmented bases via the base excision repair pathway is known to be critical for maintaining genomic stability. One enzyme that initiates base excision repair of ring-fragmented purines and some saturated pyrimidines is NEIL1, a mammalian homolog to Escherichia coli endonuclease VIII. To investigate the organismal consequences of a deficiency in NEIL1, a knockout mouse model was created. In the absence of exogenous oxidative stress, neil1 knockout (neil1-/-) and heterozygotic (neil1+/-) mice develop severe obesity, dyslipidemia, and fatty liver disease and also have a tendency to develop hyperinsulinemia. In humans, this combination of clinical manifestations, including hypertension, is known as the metabolic syndrome and is estimated to affect >40 million people in the United States. Additionally, mitochondrial DNA from neil1 -/- mice show increased levels of steady-state DNA damage and deletions relative to wild-type controls. These data suggest an important role for NEIL1 in the prevention of the diseases associated with the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)1864-1869
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number6
DOIs
StatePublished - Feb 15 2006

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DNA Glycosylases
DNA Repair
Fatty Liver
Mitochondrial DNA
Liver Diseases
Reactive Oxygen Species
Deoxyribonuclease (Pyrimidine Dimer)
Pyrimidines
Purines
Morbid Obesity
Genomic Instability
DNA
Hyperinsulinism
Dyslipidemias
Knockout Mice
Cataract
DNA Damage
Oxidative Stress
Cardiovascular Diseases
Escherichia coli

Keywords

  • DNA repair
  • Fatty liver disease
  • Mitochondria
  • Obesity
  • Oxidative stress

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. / Vartanian, Vladimir; Lowell, Brian; Minko, Irina G.; Wood, Thomas; Ceci, Jeffrey D.; George, Shakeeta; Ballinger, Scott W.; Corless, Christopher L.; McCullough, Amanda K.; Lloyd, R. Stephen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 6, 15.02.2006, p. 1864-1869.

Research output: Contribution to journalArticle

Vartanian, V, Lowell, B, Minko, IG, Wood, T, Ceci, JD, George, S, Ballinger, SW, Corless, CL, McCullough, AK & Lloyd, RS 2006, 'The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 6, pp. 1864-1869. https://doi.org/10.1073/pnas.0507444103
Vartanian, Vladimir ; Lowell, Brian ; Minko, Irina G. ; Wood, Thomas ; Ceci, Jeffrey D. ; George, Shakeeta ; Ballinger, Scott W. ; Corless, Christopher L. ; McCullough, Amanda K. ; Lloyd, R. Stephen. / The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 6. pp. 1864-1869.
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