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Cell Metab. 2014 Mar 4;19(3):484-97. doi: 10.1016/j.cmet.2014.01.013.

Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes.

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  • 1Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; Department 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.
  • 2Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
  • 3Department of Internal Medicine, Seoul National University College of Medicine, 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; Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoi-ro, Yonsu-gu, Incheon 406-813, Korea.
  • 6Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea.
  • 7Division 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.
  • 8Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; Department 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; Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Electronic address: hyosoo@snu.ac.kr.

Abstract

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-κB-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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24606903
[PubMed - indexed for MEDLINE]
PMCID:
PMC3969988
[Available on 2015/3/4]
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