• Cardiometabolic Disorder
• Inflammatory Disease

• Endocrinology
• Diabetes & Metabolic Syndrome
• Cardiometabolic Disorder
• Inflammatory Disease

Hyo-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.

Cardiometabolic 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.

One 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. Nature 2001]. In humans, elevated resistin is associated with chronic inflammation [Kaser S et al. Biochem Biophys Res Commun 2003; Silswal N et al. Biochem Biophys Res Commun 2005], vascular inflammation [Jung HS et al. Cardiovasc Res 2006] and arterial atherosclerosis. Yet, the cell receptor has remained unknown and has not been described.

In 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.

The 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.

THP-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-κB) in monocytes, and upregulated the protein level of integrin β1 and the mRNA expression of the cytokines interleukin-6, −1β, and tumor necrosis factor-alpha. All responses could be abolished by a small interfering RNA that targeted CAP 1.

These results support a scenario involving crosstalk between the monocyte cAMP, PKA signaling and NF-κB pathways, in which CAP1 acts as a receptor for resistin and regulates the resistin-induced activity of monocytes.

In support of this hypothesis, inhibition of PKA activity in vitro abolished resistin-induced activation of NF-κB and expression of inflammatory cytokines. In vivo, 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.

• © 2013 MD Conference Express®