Prof. Hermona Soreq

miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression

Hanin, G, Yayon N, Tzur Y, Haviv R, Bennett ER, Udi S, Krishnamoorthy YR, Kotsiliti E, Zangen R, Efron B, Tam J, Pappo O, Shteyer E, Pikarsky E, Heikenwalder M, Greenberg DS, Soreq H.  2017.  

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.

Journal:

Gut

Date Published:

Apr 05

Notes:

1468-3288Hanin, GeulaYayon, NadavTzur, YonatHaviv, RotemBennett, Estelle RUdi, ShiranKrishnamoorthy, Yoganathan RKotsiliti, EleniZangen, RivkaEfron, BenTam, JosephPappo, OritShteyer, EyalPikarsky, EliHeikenwalder, MathiasGreenberg, David SSoreq, HermonaJournal ArticleEnglandGut. 2017 Apr 5. pii: gutjnl-2016-312869. doi: 10.1136/gutjnl-2016-312869.