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.
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Acknowledgements
We would like to thank Jason Kim at the University of Massachusetts Mouse Metabolic Phenotyping Center (supported by NIH grant 2U2C-DK093000) for providing body composition measurements and Carla Harris at the Vanderbilt University Mouse Metabolic Phenotyping Center (supported by grant U24-DK059637) for generating the lipoprotein profiles. We would also like to acknowledge funding support from the American Heart Association grants 12SDG8840004 and 12IRG9010008 (MDH), The Ellison Medical Foundation (MDH), the National Institutes of Health and the NIA grant R01AG045351 and R56AG052568 (MDH), and the Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research supported by the National Institute of Aging (P30AG028716–01). This work was partially supported by a Canadian Institutes for Health Research grant to JDJ. FKH was supported by a Canadian Diabetes Association/American Diabetes Association Post-doctoral Fellowship (PF-3-13-4342-FH). The funding sources had no role in the conduct or presentation of this research.
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All institutional and national guidelines for the care and use of laboratory animals were followed. Animal studies were approved by the Duke Institutional Animal Care and Use Program (Protocol #A091–17-04).
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Huynh, F.K., Hu, X., Lin, Z. 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 41, 59–72 (2018). https://doi.org/10.1007/s10545-017-0069-8
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DOI: https://doi.org/10.1007/s10545-017-0069-8