Vaspin is a serine protease inhibitor that protects against adipose tissueinflammation and insulin resistance, two key drivers of adipocyte dysfunc-tion and metabolic disorders in obesity. Inhibition of target proteases suchas KLK7 has been shown to reduce adipose tissue inflammation in obesity,while vaspin binding to cell surface GRP78 has been linked to reducedobesity-induced ER stress and insulin resistance in the liver. However, themolecular mechanisms by which vaspin directly affects cellular processes inadipocytes remain unknown. Using fluorescently labeled vaspin, we foundthat vaspin is rapidly internalized by mouse and human adipocytes, but lessefficiently by endothelial, kidney, liver, and neuronal cells. Internalizationoccurs by active, clathrin-mediated endocytosis, which is dependent on vas-pin binding to the LRP1 receptor, rather than GRP78 as previously thought.This was demonstrated by competition experiments and RNAi-mediatedknock-down in adipocytes and by rescuing vaspin internalization in LRP1-deficient Pea13 cells after transfection with a functional LRP1 minireceptor.Vaspin internalization is further increased in mature adipocytes after insulin-stimulated translocation of LRP1. Although vaspin has nanomolar affinityfor LRP1 clusters II-IV, binding to cell surface heparan sulfates is requiredfor efficient LRP1-mediated internalization. Native, but not cleaved vaspin,and also vaspin polymers are efficiently endocytosed, and ultimately targetedfor lysosomal degradation. Our study provides mechanistic insight into theuptake and degradation of vaspin in adipocytes, thereby broadening ourunderstanding of its functional repertoire. We hypothesize the vaspin-LRP1axis to be an important mediator of vaspin effects not only in adipose tissuebut also in other LRP1-expressing cells.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:94162 |
| Date | 21 October 2024 |
| Creators | Tindall, Catherine A., Möhlis, Kevin, Rapöhn, Inka, Dommel, Sebastian, Riedl, Veronika, Schneekönig, Michael, Höfling, Corinna, Roßner, Steffen, Stichel, Jan, Beck-Sickinger, Annette G., Weiner, Juliane, Heiker, John T. |
| Publisher | Wiley |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 10.1111/febs.16991 |
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