SIRT7 Represses Myc Activity to Suppress ER Stress and Prevent Fatty Liver Disease
Jiyung Shin,
Ming He,
Yufei Liu,
Silvana Paredes,
Lidia Villanova,
Katharine Brown,
Xiaolei Qiu,
Noushin Nabavi,
Mary Mohrin,
Kathleen Wojnoonski,
Patrick Li,
Hwei-Ling Cheng,
Andrew J. Murphy,
David M. Valenzuela,
Hanzhi Luo,
Pankaj Kapahi,
Ronald Krauss,
Raul Mostoslavsky,
George D. Yancopoulos,
Frederick W. Alt,
Katrin F. Chua,
Danica Chen
Affiliations
Jiyung Shin
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Ming He
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Yufei Liu
Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA
Silvana Paredes
Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Lidia Villanova
Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Katharine Brown
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Xiaolei Qiu
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Noushin Nabavi
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Mary Mohrin
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Kathleen Wojnoonski
Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, CA 94609, USA
Patrick Li
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Hwei-Ling Cheng
Howard Hughes Medical Institute, The Children’s Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
Andrew J. Murphy
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
David M. Valenzuela
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
Hanzhi Luo
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
Pankaj Kapahi
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA
Ronald Krauss
Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, CA 94609, USA
Raul Mostoslavsky
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
George D. Yancopoulos
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
Frederick W. Alt
Howard Hughes Medical Institute, The Children’s Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
Katrin F. Chua
Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
Danica Chen
Program in Metabolic Biology, Nutritional Sciences, & Toxicology, University of California, Berkeley, CA 94720, USA
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.
