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Cell Rep. 2013 Nov 14;5(3):654-665. doi: 10.1016/j.celrep.2013.10.007. Epub 2013 Nov 7.

SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.

Author information

1
Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
2
Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
3
Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA.
4
Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
6
Department of Experimental Medicine, Sapienza University, Rome, Italy.
7
Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
8
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
9
Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA.
10
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
11
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
12
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
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Contributed equally

Erratum in

  • Cell Rep. 2013 Dec 12;5(5):1479.

Abstract

Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD(+)-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.

PMID:
24210820
PMCID:
PMC3888240
DOI:
10.1016/j.celrep.2013.10.007
[Indexed for MEDLINE]
Free PMC Article
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