Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin
levels and accelerated age-induced insulin resistance in multiple murine genetic
Authors Huynh FK, Hu X, Lin Z, Johnson JD, Hirschey MD
Submitted By Submitted Externally on 7/28/2017
Status Published
Journal Journal of inherited metabolic disease
Year 2017
Date Published 7/19/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 28726069
Abstract 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.

StrainDevelopment StatusCreation MethodOptions
C57BL/6-Sirt4tm1FwaCharacterizing multiple linesknockout