title: The histone methyltransferase Suv39h2 contributes to nonalcoholic steatohepatitis in mice.
abstract: Uncontrolled inflammatory response highlights the central theme of nonalcoholic steatohepatitis (NASH), a growing global pandemic. Hepatocytes and macrophages represent two major sources of hepatic inflammation during NASH pathogenesis, contributing to excessive synthesis of proinflammatory mediators. The epigenetic mechanism that accounts for the activation of hepatocytes and macrophages in this process remains obscure. Here, we report that compared to wild-type littermates, mice with a deficiency in the histone H3K9 methyltransferase suppressor of variegation 39 homolog 2 (Suv39h2, knockout) exhibited a less severe form of NASH induced by feeding with a high-fat, high-carbohydrate diet. Pro-NASH stimuli increased Suv39h2 expression in cell culture, in mice, and in human livers. In hepatocytes, Suv39h2 bound to the Sirt1 gene promoter and repressed Sirt1 transcription. Suv39h2 deficiency normalized Sirt1 expression, allowing nuclear factor kappa B/p65 to become hypoacetylated and thus dampening nuclear factor kappa B-dependent transcription of proinflammatory mediators. In macrophages, Suv39h2-mediated repression of peroxisome proliferator-activated receptor gamma transcription favored a proinflammatory M1 phenotype over an anti-inflammatory M2 phenotype, thereby elevating hepatic inflammation.
  
  
  
  Suv39h2 plays a pivotal role in the regulation of inflammatory response in hepatocytes and macrophages, contributing to NASH pathogenesis. (Hepatology 2017;65:1904-1919).
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.|Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital to Nanjing University Medical School, Nanjing, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Luyang
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Chenzhi
authors.initials: C
authors.lastname: Hao
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Inflammation and Molecular Targets, Department of Immunology, College of Medicine, Nantong University, Nantong, China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.affiliation: Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Key Laboratory of Cardiovascular Disease and Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000469:parasitology / Q000503:physiopathology; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012016:Reference Values; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1