title: Additive effects of microRNAs and transcription factors on CCL2 production in human white adipose tissue.
abstract: Adipose tissue inflammation is present in insulin-resistant conditions. We recently proposed a network of microRNAs (miRNAs) and transcription factors (TFs) regulating the production of the proinflammatory chemokine (C-C motif) ligand-2 (CCL2) in adipose tissue. We presently extended and further validated this network and investigated if the circuits controlling CCL2 can interact in human adipocytes and macrophages. The updated subnetwork predicted that miR-126/-193b/-92a control CCL2 production by several TFs, including v-ets erythroblastosis virus E26 oncogene homolog 1 (avian) (ETS1), MYC-associated factor X (MAX), and specificity protein 12 (SP1). This was confirmed in human adipocytes by the observation that gene silencing of ETS1, MAX, or SP1 attenuated CCL2 production. Combined gene silencing of ETS1 and MAX resulted in an additive reduction in CCL2 production. Moreover, overexpression of miR-126/-193b/-92a in different pairwise combinations reduced CCL2 secretion more efficiently than either miRNA alone. However, although effects on CCL2 secretion by co-overexpression of miR-92a/-193b and miR-92a/-126 were additive in adipocytes, the combination of miR-126/-193b was primarily additive in macrophages. Signals for miR-92a and -193b converged on the nuclear factor-κB pathway. In conclusion, TF and miRNA-mediated regulation of CCL2 production is additive and partly relayed by cell-specific networks in human adipose tissue that may be important for the development of insulin resistance/type 2 diabetes.
authors.affiliation: Department of Medicine, Huddinge, Lipid Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Agné
authors.initials: A
authors.lastname: Kulyté
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Belarbi
authors.forename: Silvia
authors.initials: S
authors.lastname: Lorente-Cebrián
authors.forename: Clara
authors.initials: C
authors.lastname: Bambace
authors.forename: Erik
authors.initials: E
authors.lastname: Arner
authors.forename: Carsten O
authors.initials: CO
authors.lastname: Daub
authors.forename: Per
authors.initials: P
authors.lastname: Hedén
authors.forename: Mikael
authors.initials: M
authors.lastname: Rydén
authors.forename: Niklas
authors.initials: N
authors.lastname: Mejhert
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism* / Q000502:physiology; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C494041:ETS1 protein, human; C499330:MAX protein, human; C527111:MIRN126 microRNA, human; C546818:MIRN193 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D016329:Sp1 Transcription Factor; D014157:Transcription Factors