Year: 2026
Type: article
Abstract: The lymphatic system plays a central role in lipid absorption by transporting triglyceride-rich particles called chylomicrons (CMs) from the small intestine to the systemic circulation. However, the molecular mechanism by which CMs get into the intestinal lymphatics is unknown. Here, we demonstrated that GPR182, an atypical chemokine receptor in lymphatic endothelial cells, mediates dietary fat absorption. GPR182-KO mice exhibited a selective increase in circulating high-density lipoproteins and are resistant to diet-induced obesity. GPR182 ablation in mice led to poor lipid absorption and thereby a delay in growth during development. GPR182 broadly interacted with and transported lipoproteins. Transmission electron microscopy analysis revealed that, mechanistically, loss of GPR182 prevented CMs from entering the lacteal lumen of the small intestine. Consistent with this, GPR182 blockade with mAbs protected mice from diet-induced obesity and treated existing obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption and supports GPR182 blockade as a feasible approach to treating obesity and related disorders.
DOI: 10.1172/jci200857
Authors: Zhiwei Sun, Robert J. Torphy, Emily N. Miller, Anza Darehshouri, Isaac Vigil, Taichi Terai, Eleanor Eck, Yi Sun, Yujie Guo, Dustin P. Fykstra, Elliott J. Yee, Junyi Hu, Ross M. Kedl, Erika L. Lasda, Jay R. Hesselberth, Julie A. Siegenthaler, Paul S. MacLean, Kimberley D. Bruce, Gwendalyn J. Randolph, Richard D. Schulick, Yuwen Zhu
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: Biochemistry at single-cell resolution: a new approach to understand functional heterogeneity, G5520316217, Washington University Nutrition Obesity Research Center, Biology of RNA damage and repair, The GPR171 pathway in cancer immunotherapy, The CD93 pathway and melanoma therapy, Melanoma Immunotherapy with GPR182 blockade
OpenAlex ID: W7140178915