MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1.
Human adipose tissue secretes a number of proinflammatory mediators that may contribute to the pathophysiology of obesity-related disorders. Understanding the regulatory pathways that control their production is paramount to developing effective therapeutics to treat these diseases. Using primary human adipose-derived stem cells as a source of preadipocytes and in vitro differentiated adipocytes, we found IL-8 and monocyte chemoattractant protein-1 (MCP-1) are constitutively secreted by both cell types and induced in response to serum deprivation. MicroRNA profiling revealed the rapid induction of microRNA 132 (miR-132) in these cells when switched to serum-free medium. Furthermore, miR-132 overexpression was sufficient to induce nuclear factor-kappaB translocation, acetylation of p65, and production of IL-8 and MCP-1. Inhibitors of miR-132 decreased acetylated p65 and partially inhibited the production of IL-8 and MCP-1 induced by serum deprivation. MiR-132 was shown to inhibit silent information regulator 1 (SirT1) expression through a miR-132 binding site in the 3'-untranslated region of SirT1. Thus, in response to nutritional availability, induction of miR-132 decreases SirT1-mediated deacetylation of p65 leading to activation of nuclear factor-kappaB and transcription of IL-8 and MCP-1 in primary human preadipocytes and in vitro differentiated adipocytes.
Strum
Jay C
JC
Department of Metabolic Discovery Technology Group, GlaxoSmithKline, Inc., Research Triangle Park, North Carolina 27709, USA. jaystrum@msn.com
Johnson
Jennifer H
JH
Ward
James
J
Xie
Hongbo
H
Feild
John
J
Hester
Austin
A
Alford
Alexander
A
Waters
K Michelle
KM
D020413:3' Untranslated Regions; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology; D000328:Adult; D001665:Binding Sites; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D052756:Nutritional Sciences; D056564:Sirtuin 1 / Q000378:metabolism / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology
D020413:3' Untranslated Regions; D018932:Chemokine CCL2; D018925:Chemokines; D016209:Interleukin-8; C547077:MIRN132 microRNA, human; D035683:MicroRNAs; C447939:SIRT1 protein, human; D056564:Sirtuin 1