Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation.
FASEB J, 2013/12;27(12):4940-53.
Kitamura H[1], Kimura S, Shimamoto Y, Okabe J, Ito M, Miyamoto T, Naoe Y, Kikuguchi C, Meek B, Toda C, Okamoto S, Kanehira K, Hase K, Watarai H, Ishizuka M, El-Osta A, Ohara O, Miyoshi I
Affiliations
PMID: 24005904DOI: 10.1096/fj.13-233528
Impact factor: 5.834
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.
Keywords: aP2; diabetes; epigenetic control
MeSH terms
Adipocytes; Animals; Cell Line; Chromatin; Chromatin Assembly and Disassembly; Endopeptidases; Epigenesis, Genetic; Histones; Humans; Inflammation; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Myeloid Cells; Plasminogen Activator Inhibitor 1; Serum Amyloid A Protein; Transcription Factor AP-2; Transcription, Genetic; Ubiquitin Thiolesterase; Ubiquitin-Specific Proteases
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