Aging is a major risk factor for metabolic disease and results in a decline in fatty acid oxidation, but the molecular mechanisms for this association are still unclear. The protein Sir2 (Silent Information Regulator) positively regulates aging in model organisms, and its NAD-dependent enzymatic activity connects lifespan with metabolism. Mammals have seven Sir2 homologs (sirtuins;SIRT1-7), which regulate distinct aspects of metabolism. We previously discovered that SIRT4 regulates amino acid metabolism via the inhibition of glutamate dehydrogenase (GDH). Our new results suggest that SIRT4 suppresses fatty acid metabolism, which likely involves several mechanisms, including inhibition of GDH activity in mitochondria, regulation of mitochondrial bioenergetics, and transcriptional repression of genes involved in fatty acid catabolism. We will test this hypothesis through a multi-disciplinary approach, including mouse biology, chemistry and biochemistry. First, using primary hepatocytes from SIRT4 KO mice, we will test the hypothesis that SIRT4 directly suppresses fatty acid oxidation. Then, we will investigate the effect of SIRT4 on mitochondrial energy production from amino acids and fatty acids. Second, we will investigate mechanisms that mediate the regulation of fatty acid oxidation by SIRT4. Third, we will utilize SIRT4 KO mice to test the role of SIRT4 in mammalian lifespan and in the regulation of fatty acid oxidation during aging and metabolic stress. These studies may provide important insights into the molecular regulation of fatty acid oxidation during aging.

Public Health Relevance

The regulation of declining fatty acid oxidation with age remains poorly understood. This proposal investigates the role of SIRT4, as a suppressor of fatty acid oxidation, which may mediate changes in fat metabolism during aging and metabolic dysfunction. These studies have the potential to lead to new treatments of diet and age-associated metabolic syndrome.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Finkelstein, David B
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Harvard University
Schools of Medicine
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Jeong, S M; Lee, J; Finley, L W S et al. (2015) SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1. Oncogene 34:2115-24
Jeong, Seung Min; Haigis, Marcia C (2015) Sirtuins in Cancer: a Balancing Act between Genome Stability and Metabolism. Mol Cells 38:750-8
Gonzalez Herrera, Karina N; Lee, Jaewon; Haigis, Marcia C (2015) Intersections between mitochondrial sirtuin signaling and tumor cell metabolism. Crit Rev Biochem Mol Biol 50:242-55
German, Natalie J; Haigis, Marcia C (2015) Sirtuins and the Metabolic Hurdles in Cancer. Curr Biol 25:R569-83
Janzer, Andreas; German, Natalie J; Gonzalez-Herrera, Karina N et al. (2014) Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A 111:10574-9
Jeong, Seung Min; Lee, Annie; Lee, Jaewon et al. (2014) SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem 289:4135-44
Jeong, Seung Min; Xiao, Cuiying; Finley, Lydia W S et al. (2013) SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 23:450-63
Csibi, Alfred; Fendt, Sarah-Maria; Li, Chenggang et al. (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153:840-54
Laurent, Gaƫlle; German, Natalie J; Saha, Asish K et al. (2013) SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 50:686-98
Bause, Alexandra S; Haigis, Marcia C (2013) SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol 48:634-9

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