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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01AG032375-05S1
Application #
8912115
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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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
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, Gaelle; de Boer, Vincent C J; Finley, Lydia W S et al. (2013) SIRT4 represses peroxisome proliferator-activated receptor * activity to suppress hepatic fat oxidation. Mol Cell Biol 33:4552-61
Laurent, Gaelle; 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
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
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Finley, Lydia W S; Lee, Jaewon; Souza, Amanda et al. (2012) Skeletal muscle transcriptional coactivator PGC-1? mediates mitochondrial, but not metabolic, changes during calorie restriction. Proc Natl Acad Sci U S A 109:2931-6
Finley, Lydia W S; Haas, Wilhelm; Desquiret-Dumas, Valerie et al. (2011) Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One 6:e23295

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