한빛사 논문
Abstract
Sahmin Lee,1,2,9 Hyun-Chae Lee,3,9 Yoo-Wook Kwon,3,9 Sang Eun Lee,1 Youngjin Cho,1 Joonoh Kim,3 Soobeom Lee,3 Ju-Young Kim,3 Jaewon Lee,3 Han-Mo Yang,1 Inhee Mook-Jung,4 Ky-Youb Nam,5,6 Junho Chung,7 Mitchell A. Lazar,8 and Hyo-Soo Kim1,2,3,*
1Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
2Department of Molecular Medicine & Biopharmaceutical Science, Graduate School of Convergence Science and Technology and College of Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea
3Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
4Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
5Bioinformatics & Molecular Design Research Center, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea
6Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoi-ro, Yonsu-gu, Incheon 406-813, Korea
7Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea
8Division of Endocrinology, Diabetes, and Metabolism, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, 12-102 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
9These authors contributed equally to this work
*Correspondence: Hyo-Soo Kim
Summary
Human resistin is a cytokine that induces low-grade inflammation by stimulating monocytes. Resistin-mediated chronic inflammation can lead to obesity, atherosclerosis, and other cardiometabolic diseases. Nevertheless, the receptor for human resistin has not been clarified. Here, we identified adenylyl cyclase-associated protein 1 (CAP1) as a functional receptor for human resistin and clarified its intracellular signaling pathway to modulate inflammatory action of monocytes. We found that human resistin directly binds to CAP1 in monocytes and upregulates cyclic AMP (cAMP) concentration, protein kinase A (PKA) activity, and NF-B-related transcription of inflammatory cytokines. Overexpression of CAP1 in monocytes enhanced the resistin-induced increased activity of the cAMP-dependent signaling. Moreover, CAP1-overexpressed monocytes aggravated adipose tissue inflammation in transgenic mice that express human resistin from their monocytes. In contrast, suppression of CAP1 expression abrogated the resistin-mediated inflammatory activity both in vitro and in vivo. Therefore, CAP1 is the bona fide receptor for resistin leading to inflammation in humans.
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