RT Journal Article
SR Electronic
T1 miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1124
OP 1134
DO 10.1136/gutjnl-2016-312869
VO 67
IS 6
A1 Geula Hanin
A1 Nadav Yayon
A1 Yonat Tzur
A1 Rotem Haviv
A1 Estelle R Bennett
A1 Shiran Udi
A1 Yoganathan R Krishnamoorthy
A1 Eleni Kotsiliti
A1 Rivka Zangen
A1 Ben Efron
A1 Joseph Tam
A1 Orit Pappo
A1 Eyal Shteyer
A1 Eli Pikarsky
A1 Mathias Heikenwalder
A1 David S Greenberg
A1 Hermona Soreq
YR 2018
UL http://gut.bmj.com/content/67/6/1124.abstract
AB 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.