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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ECardiometabolic disease is the collective term used to describe events that occur due to cardiovascular disease, diabetes, and obesity. Proinflammatory and proatherogenic pathways are also related to obesity and can contribute to insulin resistance and atherosclerosis. This article reports on the cloning of the receptor for resistin, and its involvement in chronic inflammation and cardiometabolic disease.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiometabolic Disorder\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiometabolic Disorder\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EHyo-Soo Kim, MD, PhD, Seoul National University Hospital, Seoul, South Korea, reported on the cloning of the receptor for resistin, and its involvement in chronic inflammation and cardiometabolic disease.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ECardiometabolic disease is the collective term used to describe events that occur due to cardiovascular disease, diabetes, and obesity. Proinflammatory and proatherogenic pathways are also related to obesity and can contribute to insulin resistance and atherosclerosis. Chronic lipid loading and cellular stress may also lead to enlargement of adipocytes. The hypertrophic cells respond to inflammation by becoming insulin resistant, driving the metabolic syndrome.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EOne of the implicated molecules is resistin, a cytokine that is secreted from cells such as adipocytes in mice and human monocytes and macrophages. Resistin increases the level of low-density lipoprotein cholesterol leading to the development of atherosclerosis. Increased resistin production has also been linked with obesity in a mouse model [Steppan CM et al. \u003Cem\u003ENature\u003C\/em\u003E 2001]. In humans, elevated resistin is associated with chronic inflammation [Kaser S et al. \u003Cem\u003EBiochem Biophys Res Commun\u003C\/em\u003E 2003; Silswal N et al. \u003Cem\u003EBiochem Biophys Res Commun\u003C\/em\u003E 2005], vascular inflammation [Jung HS et al. \u003Cem\u003ECardiovasc Res\u003C\/em\u003E 2006] and arterial atherosclerosis. Yet, the cell receptor has remained unknown and has not been described.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn order to characterize the resistin receptor, a fusion protein was constructed that contained human resistin with mouse Fc, allowing expression of resistin in transfected HEK cells. Used as a ligand, the human resistin bound to a 55 kDa protein in human monocytes. The protein was identified as adenylyl cyclase-associated protein 1 (CAP1). Immunofluorescence staining showed the membrane localization of CAP1 in THP-1 human monocytes. Fluorescence-activated cell sorting revealed increased CAP1 in monocytes exposed to resistin. Finally, immunofluorescent antibodies to CAP1 and resistin were found to be co-localized in the monocyte membrane.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EThe physical association between CAP 1 and resistin was determined conclusively using a variety of experimental approaches. The site of resistin binding in the 3 functional domains of CAP1 was determined using deletion mutants lacking the adenylyl cyclase-binding domain, proline-rich SH3 binding domain, and actin-binding domain. The proline-rich domain was implicated as the active site.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003ETHP-1 monocytes treated with resistin displayed a time-dependent increase in the levels of cAMP, consistent with the known role of CAP1 in the yeast adenylyl cyclase complex. Resistin increased the production of protein kinase A (PKA) and nuclear factor-kappa B (NF-\u03baB) in monocytes, and upregulated the protein level of integrin \u03b21 and the mRNA expression of the cytokines interleukin-6, \u22121\u03b2, and tumor necrosis factor-alpha. All responses could be abolished by a small interfering RNA that targeted CAP 1.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EThese results support a scenario involving crosstalk between the monocyte cAMP, PKA signaling and NF-\u03baB pathways, in which CAP1 acts as a receptor for resistin and regulates the resistin-induced activity of monocytes.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EIn support of this hypothesis, inhibition of PKA activity \u003Cem\u003Ein vitro\u003C\/em\u003E abolished resistin-induced activation of NF-\u03baB and expression of inflammatory cytokines. \u003Cem\u003EIn vivo\u003C\/em\u003E, expression of human resistin in mice demonstrated that CAP1 overexpression significantly enhanced monocyte migration to resistin, macrophage infiltration, and expression of cytokines. All were abrogated by curtailed CAP1 expression. Further work is needed to define the cellular pathways associated with this receptor; however, CAP1 may become a novel target in the treatment of inflammatory diseases such as atherosclerosis.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/16\/7.1.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznm21\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}