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Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds.

Publication ,  Journal Article
Huynh, FK; Hu, X; Lin, Z; Johnson, JD; Hirschey, MD
Published in: J Inherit Metab Dis
January 2018

Several inherited metabolic disorders are associated with an accumulation of reactive acyl-CoA metabolites that can non-enzymatically react with lysine residues to modify proteins. While the role of acetylation is well-studied, the pathophysiological relevance of more recently discovered acyl modifications, including those found in inherited metabolic disorders, warrants further investigation. We recently showed that sirtuin 4 (SIRT4) removes glutaryl, 3-hydroxy-3-methylglutaryl, 3-methylglutaryl, and 3-methylglutaconyl modifications from lysine residues. Thus, we used SIRT4 knockout mice, which can accumulate these novel post-translational modifications, as a model to investigate their physiological relevance. Since SIRT4 is localized to mitochondria and previous reports have shown SIRT4 influences metabolism, we thoroughly characterized glucose and lipid metabolism in male and female SIRT4KO mice across different genetic backgrounds. While only minor perturbations in overall lipid metabolism were observed, we found SIRT4KO mice consistently had elevated glucose- and leucine-stimulated insulin levels in vivo and developed accelerated age-induced insulin resistance. Importantly, elevated leucine-stimulated insulin levels in SIRT4KO mice were dependent upon genetic background since SIRT4KO mice on a C57BL/6NJ genetic background had elevated leucine-stimulated insulin levels but not SIRT4KO mice on the C57BL/6J background. Taken together, the data suggest that accumulation of acyl modifications on proteins in inherited metabolic disorders may contribute to the overall metabolic dysfunction seen in these patients.

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Published In

J Inherit Metab Dis

DOI

EISSN

1573-2665

Publication Date

January 2018

Volume

41

Issue

1

Start / End Page

59 / 72

Location

United States

Related Subject Headings

  • Up-Regulation
  • Sirtuins
  • Protein Processing, Post-Translational
  • Phenotype
  • Mitochondrial Proteins
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, 129 Strain
  • Metabolism, Inborn Errors
  • Male
 

Citation

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Huynh, F. K., Hu, X., Lin, Z., Johnson, J. D., & Hirschey, M. D. (2018). Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds. J Inherit Metab Dis, 41(1), 59–72. https://doi.org/10.1007/s10545-017-0069-8
Huynh, Frank K., Xiaoke Hu, Zhihong Lin, James D. Johnson, and Matthew D. Hirschey. “Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds.J Inherit Metab Dis 41, no. 1 (January 2018): 59–72. https://doi.org/10.1007/s10545-017-0069-8.
Huynh, Frank K., et al. “Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds.J Inherit Metab Dis, vol. 41, no. 1, Jan. 2018, pp. 59–72. Pubmed, doi:10.1007/s10545-017-0069-8.
Journal cover image

Published In

J Inherit Metab Dis

DOI

EISSN

1573-2665

Publication Date

January 2018

Volume

41

Issue

1

Start / End Page

59 / 72

Location

United States

Related Subject Headings

  • Up-Regulation
  • Sirtuins
  • Protein Processing, Post-Translational
  • Phenotype
  • Mitochondrial Proteins
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, 129 Strain
  • Metabolism, Inborn Errors
  • Male