@article {Haningutjnl-2016-312869, author = {Geula Hanin and Nadav Yayon and Yonat Tzur and Rotem Haviv and Estelle R Bennett and Shiran Udi and Yoganathan R Krishnamoorthy and Eleni Kotsiliti and Rivka Zangen and Ben Efron and Joseph Tam and Orit Pappo and Eyal Shteyer and Eli Pikarsky and Mathias Heikenwalder and David S Greenberg and Hermona Soreq}, title = {miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression}, elocation-id = {gutjnl-2016-312869}, year = {2017}, doi = {10.1136/gutjnl-2016-312869}, publisher = {BMJ Publishing Group}, abstract = {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.}, issn = {0017-5749}, URL = {https://gut.bmj.com/content/early/2017/04/05/gutjnl-2016-312869}, eprint = {https://gut.bmj.com/content/early/2017/04/05/gutjnl-2016-312869.full.pdf}, journal = {Gut} }