Abstract
How the pro-longevity enzyme SIRT6 coordinates between various metabolic pathways is still obscure. Here, Naiman et al. show that SIRT6 activates PPARα to promote fatty acid beta oxidation and inhibit pyruvate oxidation during fasting. This ultimately decides the energy source under nutrient-limited conditions, promoting fat usage over other energy sources.
Original language | English |
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Pages (from-to) | 4127-4143.e8 |
Journal | Cell Reports |
Volume | 29 |
Issue number | 12 |
DOIs | |
State | Published - 17 Dec 2019 |
Bibliographical note
Publisher Copyright:© 2019 The Authors
Funding
We thank members of the Cohen lab for their helpful input and their comments on the manuscript. We also thank Raul Mostoslavsky (HMS) for his gift of the SIRT6 HZ mice. We thank Tamar Geiger and Michal Harel (TAU) for help with SILAC experiments and Avia Cohen for preparing the graphical abstract. This work was supported by the following funding sources: the Israel Science Foundation ( 621/13 and 777/16 ) (H.Y.C.), I-Core Foundation ( 41/11 ) (H.Y.C. and S.N.), the Economic and Social Fund for Development ( ESFD ) (H.Y.C.), D-Cure (H.Y.C.), Israel Cancer Association ( 2016-0103 ) (H.Y.C.), the Sagol Healthy Longevity Center ( HEALS ) (H.Y.C.), Israel Cancer Research Fund ( ICRF ) (H.Y.C.) and the U.S.-Israel Binational Science Foundation ( BSF ) (H.Y.C.), the Laura and Isaac Perlmutter Fund for supporting the Technion’s metabolomics facility (E.G.), the National Institutes of Health ( NIH ), and NIA grant R01AG045351 (M.D.H.). F.K.H. was supported by an American Diabetes Association/Canadian Diabetes Association post-doctoral fellowship ( PF-3-13-4342-FH ). We thank members of the Cohen lab for their helpful input and their comments on the manuscript. We also thank Raul Mostoslavsky (HMS) for his gift of the SIRT6 HZ mice. We thank Tamar Geiger and Michal Harel (TAU) for help with SILAC experiments and Avia Cohen for preparing the graphical abstract. This work was supported by the following funding sources: the Israel Science Foundation (621/13 and 777/16) (H.Y.C.), I-Core Foundation (41/11) (H.Y.C. and S.N.), the Economic and Social Fund for Development (ESFD) (H.Y.C.), D-Cure (H.Y.C.), Israel Cancer Association (2016-0103) (H.Y.C.), the Sagol Healthy Longevity Center (HEALS) (H.Y.C.), Israel Cancer Research Fund (ICRF) (H.Y.C.) and the U.S.-Israel Binational Science Foundation (BSF) (H.Y.C.), the Laura and Isaac Perlmutter Fund for supporting the Technion's metabolomics facility (E.G.), the National Institutes of Health (NIH), and NIA grant R01AG045351 (M.D.H.). F.K.H. was supported by an American Diabetes Association/Canadian Diabetes Association post-doctoral fellowship (PF-3-13-4342-FH). H.Y.C. planned experiments, analyzed the results, and wrote the manuscript, which was reviewed by all of the authors. S.N. planned and performed experiments, analyzed the results, and wrote the manuscript. F.K.H. O.R.I. and M.D.H. performed and analyzed the metabolomics and palmitate labeling experiments. I.A. and E.G. performed and analyzed the fasting metabolomics experiments. R.G. and N.T. performed immunoprecipitation experiments. Y.G. and D.G. performed and analyzed microfluidics experiments. Y.S. and A.R. performed ChIP experiments. Y.K. helped prepare figures. L.N. and B.L. performed luciferase experiments. M.Y.A. performed SIRT6 in vitro activity and binding assays. A.A.G. helped with mouse dissections. O.Y. and T.D. ran RNA-seq and performed raw data analysis, respectively. R.A.H. provided expertise with respect to interpretation of metabolomics data and made substantial contributions to improving the studies. H.C. advises SirTLab Ltd.
Funders | Funder number |
---|---|
D-Cure | |
ESFD | |
HEALS | |
I-Core Foundation | 41/11 |
M.D.H. | |
S.N. | |
Sagol Healthy Longevity Center | |
Technion’s | |
U.S.-Israel Binational Science Foundation | |
National Institutes of Health | |
National Institute on Aging | R01AG045351 |
National Institute of Diabetes and Digestive and Kidney Diseases | R01DK115568 |
Israel Cancer Research Fund | |
American Association of Diabetes Educators | PF-3-13-4342-FH |
Arab Fund for Economic and Social Development | |
United States-Israel Binational Science Foundation | |
Israel Cancer Association | 2016-0103 |
Israel Science Foundation | 621/13, 777/16 |
Technion-Israel Institute of Technology |
Keywords
- PPARα
- SIRT6
- beta-oxidation
- deacetylase
- fasting
- liver
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