SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα
Authors: Matan Y Avivi
Liat Nahum
Orly Yaron
Olga R Ilkayeva
Ifat Abramovich
Yair Glick
Robert A Harris
Asael Roichman
Eyal Gottlieb
Noga Touitou
Yael Shahar
Tirza Doniger
Frank K Huynh
Matthew D Hirschey
Doron Gerber
Shoshana Naiman
Asaf A Gertler
Haim Y Cohen
Reuven Gil
Batia Lerrer
Yariv Kanfi
Journal: Cell reports (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: PPARα; SIRT6; beta-oxidation; deacetylase; fasting
Affiliations: Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel., 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., 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., The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 1 Efron Street, Bat Galim, Haifa, Israel., Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA., 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., Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan 5290002, Israel. Electronic address: .

Abstract:  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. 

Retracted: No

PubPeer comments:
 ![file] Several lanes are cropped, as indicated with red boxes. , 
 #1 I popped over to the originals and saw some sharp-sided bands, so you might well be onto something here, *Ceratocystis*? And there I was, under the impression that, in this day and age, Cell Press wanted original data to be deposited at Mendeley Data for all their hot new papers https: data.mendeley.com But this paper doesnu2019t say so, so perhaps I am confused about this? Even so, *Ceratocystis*, maybe you would want to check whether any u201coriginalu201d WB data has been deposited over there, just in case? You would think by now that Cell Press editors, no matter how visually challenged, would want all WB original data to be made available as a matter of course. How else to protect themselves? , 
 Dear Pubpeer colleagues, Thank you very much for your comments and for drawing our attention to figure 4B. Below please find files with the original raw data for each WB presented in this figure. As you can see, there are no cropped lanes. Moreover, we submitted the paper to Cell Reports with all of the raw data. We will recheck with the editorial office if they uploaded it and if not we will do so. Please donu2019t hesitate to contact us if you have any questions, Haim ![file] ![file] ![file] ![file] ![file] ![file] ![file] ![file] ![file] ![file] ,