GPR182 is a lipoprotein receptor for dietary fat absorption

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 knockout mice exhibit a selective increase in circulating high-density lipoproteins and are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 broadly interacts with and transports lipoproteins. Transmission electron microscopy analysis reveals that mechanistically, loss of GPR182 prevents CMs from entering the lacteal lumen of the small intestine. Consistent with this, GPR182 blockade with monoclonal antibodies protects mice from diet- induced obesity and treats 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 treat obesity and related disorders.