TY - JOUR T1 - miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression JF - Gut JO - Gut DO - 10.1136/gutjnl-2016-312869 SP - gutjnl-2016-312869 AU - Geula Hanin AU - Nadav Yayon AU - Yonat Tzur AU - Rotem Haviv AU - Estelle R Bennett AU - Shiran Udi AU - Yoganathan R Krishnamoorthy AU - Eleni Kotsiliti AU - Rivka Zangen AU - Ben Efron AU - Joseph Tam AU - Orit Pappo AU - Eyal Shteyer AU - Eli Pikarsky AU - Mathias Heikenwalder AU - David S Greenberg AU - Hermona Soreq Y1 - 2017/04/05 UR - http://gut.bmj.com/content/early/2017/04/05/gutjnl-2016-312869.abstract N2 - 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. ER -