RESUMO
Low density lipoprotein receptor-related protein 1 (LRP1) is indispensable for embryonic development. Comparing different genetically engineered mouse models, we found that expression of Lrp1 is essential in the embryo proper. Loss of LRP1 leads to lethal vascular defects with lack of proper investment with mural cells of both large and small vessels. We further demonstrate that LRP1 modulates Gi-dependent sphingosine-1-phosphate (S1P) signaling and integrates S1P and PDGF-BB signaling pathways, which are both crucial for mural cell recruitment, via its intracellular domain. Loss of LRP1 leads to a lack of S1P-dependent inhibition of RAC1 and loss of constraint of PDGF-BB-induced cell migration. Our studies thus identify LRP1 as a novel player in angiogenesis and in the recruitment and maintenance of mural cells. Moreover, they reveal an unexpected link between lipoprotein receptor and sphingolipid signaling that, in addition to angiogenesis during embryonic development, is of potential importance for other targets of these pathways, such as tumor angiogenesis and inflammatory processes.
Assuntos
Desenvolvimento Embrionário/fisiologia , Lisofosfolipídeos/metabolismo , Neovascularização Fisiológica/fisiologia , Receptores de LDL/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/análogos & derivados , Proteínas Supressoras de Tumor/metabolismo , Animais , Becaplermina , Western Blotting , Movimento Celular/fisiologia , Engenharia Genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Imuno-Histoquímica , Hibridização In Situ , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Camundongos , Microscopia Eletrônica , Proteínas Proto-Oncogênicas c-sis/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Esfingosina/metabolismoRESUMO
The low-density lipoprotein receptor-related protein LRP1 is a cell surface receptor with functions in diverse physiological pathways, including lipid metabolism. Here we show that LRP1-deficient fibroblasts accumulate high levels of intracellular cholesterol and cholesteryl-ester when stimulated for adipocyte differentiation. We demonstrate that LRP1 stimulates a canonical Wnt5a signaling pathway that prevents cholesterol accumulation. Moreover, we show that LRP1 is required for lipolysis and stimulates fatty acid synthesis independently of the noradrenergic pathway, through inhibition of GSK3beta and its previously unknown target acetyl-CoA carboxylase (ACC). As a result of ACC inhibition, mature LRP1-deficient adipocytes of adult mice are hypotrophic, and lower uptake of fatty acids into adipose tissue leads to their redistribution to the liver. These results establish LRP1 as a novel integrator of adipogenic differentiation and fat storage signals.
