Endothelial LRP1 regulates metabolic responses by acting as a co-activator of PPARγ

• Published in: Nature communications Vol. 8; no. 1; p. 14960
• Main Authors: Mao, Hua, Lockyer, Pamela, Li, Luge, Ballantyne, Christie M., Patterson, Cam, Xie, Liang, Pi, Xinchun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.04.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/95; 38/1; 38/22; 38/70; 38/77; 38/88; 45/15; 45/70; 59/5; 631/337/572/2102; 631/443/319/1642/2037; 631/80/86/388; 64/60; 82/29; Adipokines - blood; Animals; CD36 Antigens - metabolism; Cholesterol - metabolism; Diet, High-Fat; Endocytosis - drug effects; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene Expression Regulation - drug effects; Glucose Tolerance Test; HEK293 Cells; Humanities and Social Sciences; Humans; Insulin Resistance; Lipids - blood; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Organ Specificity - drug effects; Physical Conditioning, Animal; PPAR gamma - metabolism; Protein Binding - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Thiazolidinediones - pharmacology; Transcription, Genetic; Weight Gain
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14960

Low-density lipoprotein receptor-related protein 1 (LRP1) regulates lipid and glucose metabolism in liver and adipose tissue. It is also involved in central nervous system regulation of food intake and leptin signalling. Here we demonstrate that endothelial Lrp1 regulates systemic energy homeostasis. Mice with endothelial-specific Lrp1 deletion display improved glucose sensitivity and lipid profiles combined with increased oxygen consumption during high-fat-diet-induced obesity. We show that the intracellular domain of Lrp1 interacts with the nuclear receptor Pparγ, a central regulator of lipid and glucose metabolism, acting as its transcriptional co-activator in endothelial cells. Therefore, Lrp1 not only acts as an endocytic receptor but also directly participates in gene transcription. Our findings indicate an underappreciated functional role of endothelium in maintaining systemic energy homeostasis. LDL receptor-related protein 1 (LRP1) is an endocytic receptor involved in cell signalling and energy homeostasis. Here Mao et al . demonstrate that endothelial Lrp1 modulates lipid and glucose metabolism by binding the nuclear receptor Pparγ and promoting its transcriptional activity.