title: miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression.
abstract: Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes.
  
  
  
  We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts.
  
  
  
  Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases inlipogenesis and lipid accumulation-related transcripts. Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype.
  
  
  
  Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Geula
authors.initials: G
authors.lastname: Hanin
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Nadav
authors.initials: N
authors.lastname: Yayon
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Yonat
authors.initials: Y
authors.lastname: Tzur
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Haviv
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Bennett
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Udi
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yoganathan R
authors.initials: YR
authors.lastname: Krishnamoorthy
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Kotsiliti
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Zangen
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Efron
authors.affiliation: Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Joseph
authors.initials: J
authors.lastname: Tam
authors.affiliation: The Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Pappo
authors.affiliation: The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Shteyer
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.|The Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: David S
authors.initials: DS
authors.lastname: Greenberg
authors.affiliation: The Silberman Institute of Life Sciences and the Edmond and Lily Safra Center for Brain Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem, Israel.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
mesh_terms: D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy / Q000209:etiology; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology
chemical_list: D008055:Lipids; C547077:MIRN132 microRNA, human; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense
keywords: FATTY LIVER; NONALCOHOLIC STEATOHEPATITIS