Journal
CELL REPORTS
Volume 5, Issue 3, Pages 654-665Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.10.007
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Funding
- National Institutes of Health [R01AG040990, R01AG028867, 3T32DK007217-36S1, T32 AG000266]
- Searle Scholars Program
- Ellison Medical Foundation
- Glenn Foundation
- American Heart Association
- UCOP TRDRP
- Hellman Family Faculty Fund
- National Science Foundation
- Siebel Stem Cell Institute
- Department of Veterans Affairs
- Italian Foundation for Cancer Research
- Associazione Italiana per la Ricerca sul Cancro Funding Source: Custom
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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.
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