%0 Journal Article %A Geula Hanin %A Nadav Yayon %A Yonat Tzur %A Rotem Haviv %A Estelle R Bennett %A Shiran Udi %A Yoganathan R Krishnamoorthy %A Eleni Kotsiliti %A Rivka Zangen %A Ben Efron %A Joseph Tam %A Orit Pappo %A Eyal Shteyer %A Eli Pikarsky %A Mathias Heikenwalder %A David S Greenberg %A Hermona Soreq %T miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression %D 2017 %R 10.1136/gutjnl-2016-312869 %J Gut %P gutjnl-2016-312869 %X Objective 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.Design 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.Results 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 in lipogenesis 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.Conclusions 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. %U https://gut.bmj.com/content/gutjnl/early/2017/04/05/gutjnl-2016-312869.full.pdf