SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα

Shoshana Naiman, Frank K. Huynh, Reuven Gil, Yair Glick, Yael Shahar, Noga Touitou, Liat Nahum, Matan Y. Avivi, Asael Roichman, Yariv Kanfi, Asaf A. Gertler, Tirza Doniger, Olga R. Ilkayeva, Ifat Abramovich, Orly Yaron, Batia Lerrer, Eyal Gottlieb, Robert A. Harris, Doron Gerber, Matthew D. HirscheyHaim Y. Cohen

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

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 languageEnglish
Pages (from-to)4127-4143.e8
JournalCell Reports
Volume29
Issue number12
DOIs
StatePublished - 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.

FundersFunder number
D-Cure
ESFD
HEALS
I-Core Foundation41/11
M.D.H.
S.N.
Sagol Healthy Longevity Center
Technion’s
U.S.-Israel Binational Science Foundation
National Institutes of Health
National Institute on AgingR01AG045351
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK115568
Israel Cancer Research Fund
American Association of Diabetes EducatorsPF-3-13-4342-FH
Arab Fund for Economic and Social Development
United States-Israel Binational Science Foundation
Israel Cancer Association2016-0103
Israel Science Foundation621/13, 777/16
Technion-Israel Institute of Technology

    Keywords

    • PPARα
    • SIRT6
    • beta-oxidation
    • deacetylase
    • fasting
    • liver

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