GPR182 is a lipoprotein receptor for dietary fat absorption
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
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
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Research Article Metabolism Vascular biology

GPR182 is a lipoprotein receptor for dietary fat absorption

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.

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

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Figure 1

Gpr182–/– mice are resistant to diet-induced obesity.

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Gpr182–/– mice are resistant to diet-induced obesity. Seven-week-old ma...
Seven-week-old male WT and Gpr182–/– mice were fed a chow diet or a HFD for 16 weeks. (A) BW was followed weekly. (B) Representative images of mice following 16 weeks of HFD or chow feeding (scale bars: 1 cm) and (C) BW gain. (D) Fat percentages for WT and Gpr182–/– mice fed a HFD were calculated. eWAT, epicardial WAT; iWAT, inguinal WAT; sWAT, subcutaneous WAT; aWAT, axillary WAT. (E) H&E staining of gWAT from Gpr182–/– and control mice on a HFD (scale bars: 200 μm) and adipocyte sizes. (F) Representative images of livers from Gpr182–/– and WT mice on a HFD (scale bar: 1 cm) and liver weights. (G) H&E and Oil Red O staining of liver tissues from Gpr182–/– and WT control mice on a HFD. Scale bars: 200 μm. Insets, original magnification: ×400. TAG levels in the liver (H) and serum levels of TAG (I), FFA (J), glucose (K), insulin (L), and leptin (M) in Gpr182–/– and control WT mice on a HFD were quantified. Chow diet: n = 5; HFD: n = 8–9, pooled from 2 independent experiments. Data represent the mean ± SEM. An unpaired, 2-tailed Student’s t test was used to compare the means of 2 groups (C–M). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.