title: Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation.
abstract: Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (∼6-fold) and SAA3 (∼15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P<0.01), which was consistent with a ∼40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (>2.1-fold), methylation of histone H3 lysine 4 (>4.5-fold), and acetylation of histone H4 (>2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.
authors.affiliation: 1Department of Comparative and Experimental Medicine, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. ktmr@med.nagoya-cu.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kimura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Shimamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ito
authors.forename: Tomomi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Naoe
authors.forename: Chisato
authors.initials: C
authors.lastname: Kikuguchi
authors.forename: Bob
authors.initials: B
authors.lastname: Meek
authors.forename: Chitoku
authors.initials: C
authors.lastname: Toda
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kanehira
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watarai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ishizuka
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Miyoshi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D000685:Serum Amyloid A Protein; D050656:Transcription Factor AP-2; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse
keywords: aP2; diabetes; epigenetic control