title: SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease.
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.
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Jiyung
authors.initials: J
authors.lastname: Shin
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.|Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Ming
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Molecular & Cell Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.|Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Silvana
authors.initials: S
authors.lastname: Paredes
authors.affiliation: Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.|Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.|Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Villanova
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Katharine
authors.initials: K
authors.lastname: Brown
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Noushin
authors.initials: N
authors.lastname: Nabavi
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Mohrin
authors.affiliation: Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Wojnoonski
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Li
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Luo
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
authors.affiliation: Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Krauss
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA.|Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.affiliation: Department of Medicine, Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA 94305, USA.|Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
authors.affiliation: Program in Metabolic Biology, Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
authors.forename: Danica
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D016259:Genes, myc; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D016271:Proto-Oncogene Proteins c-myc; C510661:SIRT7 protein, human; C539736:Sirt7 protein, mouse; D037761:Sirtuins