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. Hirschey,
Haim Y. Cohen
Affiliations
Shoshana Naiman
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Frank K. Huynh
Department of Biological Sciences, San Jose State University, San Jose, CA 95192, USA; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
Reuven Gil
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Yair Glick
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Yael Shahar
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Noga Touitou
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Liat Nahum
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Matan Y. Avivi
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Asael Roichman
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Yariv Kanfi
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Asaf A. Gertler
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Tirza Doniger
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Olga R. Ilkayeva
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
Ifat Abramovich
The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, 1 Efron Street, Bat Galim, Haifa, Israel
Orly Yaron
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Batia Lerrer
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel
Eyal Gottlieb
The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, 1 Efron Street, Bat Galim, Haifa, Israel
Robert A. Harris
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
Doron Gerber
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel; Bar Ilan Institute for Nanotechnology and Advanced Materials, Bar Ilan University, Ramat Gan 5290002, Israel
Matthew D. Hirschey
Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA
Haim Y. Cohen
Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel; Corresponding author
Summary: The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver. : 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. Keywords: SIRT6, PPARα, beta-oxidation, liver, deacetylase, fasting
