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Transcription Factor Activating Protein-2β: A Positive Regulator of Monocyte Chemoattractant Protein-1 Gene Expression

Division of Endocrinology and Metabolism (M.K., H.M., T.O., S.U., K.I., K.M., Y.Na., Y.Ni., A.K.), Department of Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan; and Center for Genomic Medicine (S.M.), Laboratory for Endocrinology and Metabolism, The Institute of Physical and Chemical Research, Kanagawa 230-0045, Japan.

Address all correspondence and requests for reprints to: Hiroshi Maegawa, M.D., Department of Medicine, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan. E-mail: maegawa{at}belle.shiga-med.ac.jp.

We previously reported an association between the activating protein (AP)-2β transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2β showed stronger AP-2β expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2β leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study, we found that overexpression of AP-2β in 3T3-L1 adipocytes accelerated the promoter activity of monocyte chemoattractant protein-1 (MCP-1) and subsequently increased both mRNA and protein expression and protein secretion. Furthermore, knockdown of endogenous AP-2β by RNA interference reduced the mRNA and the protein expression of MCP-1. EMSAs and chromatin immunoprecipitation assays revealed specific binding of AP-2β to MCP-1 promoter regions, in vitro and in vivo. Additionally, site-directed mutagenesis of the AP-2 binding site located at –137 to –129 relative to the transcription start site markedly diminished MCP-1 promoter activity, whereas other putative AP-2 binding sites did not. Our results clearly show that AP-2β directly enhanced MCP-1 secretion by binding to its promoter. Thus, we propose that AP-2β positively regulates MCP-1 expression; subsequently contributes to the infiltration of macrophages to adipose tissue; and leads to insulin resistance, type 2 diabetes, and cardiovascular diseases.