GPR182 is a lipoprotein receptor for dietary fat absorption

Sun, Z.; Torphy, R. J.; Miller, E. N.; Darehshouri, A.; Vigil, I.; Terai, T.; Eck, E.; Sun, Y.; Guo, Y.; Yee, E. J.; Hu, J.; Kedl, R. M.; Lasda, E. L.; Hesselberth, J. R.; MacLean, P.; Bruce, K. D.; Randolph, G. J.; Schulick, R. D.; Zhu, Y.

doi:10.1101/2025.02.03.634329

bioRxiv · 10.1101/2025.02.03.634329

GPR182 is a lipoprotein receptor for dietary fat absorption

Sun, Z.·Torphy, R. J.·Miller, E. N.·Darehshouri, A.·Vigil, I.·Terai, T.·Eck, E.·Sun, Y.·Guo, Y.·Yee, E. J.·Hu, J.·Kedl, R. M.·Lasda, E. L.·Hesselberth, J. R.·MacLean, P.·Bruce, K. D.·Randolph, G. J.·Schulick, R. D.·Zhu, Y.

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Abstract

The lymphatic system plays a central role in lipid absorption, which transports chylomicrons from the small intestine to the circulation. However, the molecular mechanism by which chylomicrons get into the intestinal lymphatics is unknown. Here we demonstrated that GPR182, a receptor in lymphatic endothelial cells (LECs), mediates dietary fat absorption. GPR182 knockout mice are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 binds and endocytoses lipoproteins broadly. Mechanistically, loss of GPR182 prevents chylomicrons from entering the lacteal lumen of the small intestine. GPR182 blockage with a monoclonal antibody (mAb) protects mice from dietary induced obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption.

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Sun, Z., Torphy, R. J., Miller, E. N., Darehshouri, A., Vigil, I., Terai, T., Eck, E., Sun, Y., Guo, Y., Yee, E. J., Hu, J., Kedl, R. M., Lasda, E. L., Hesselberth, J. R., MacLean, P., Bruce, K. D., Randolph, G. J., Schulick, R. D., Zhu, Y.. 2025-02-07. GPR182 is a lipoprotein receptor for dietary fat absorption. https://doi.org/10.1101/2025.02.03.634329

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