TY - JOUR
T1 - Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation
AU - El Asmar, Zeina
AU - Terrand, Jérome
AU - Jenty, Marion
AU - Host, Lionel
AU - Mlih, Mohamed
AU - Zerr, Aurélie
AU - Justiniano, Hélène
AU - Matz, Rachel L.
AU - Boudier, Christian
AU - Scholler, Estelle
AU - Garnier, Jean Marie
AU - Bertaccini, Diego
AU - Thiersé, Danièle
AU - Schaeffer, Christine
AU - Van Dorsselaer, Alain
AU - Herz, Joachim
AU - Bruban, Véronique
AU - Boucher, Philippe
N1 - Funding Information:
This work was supported by grants from Fondation de France, Fondation pour la Recherche Médicale (FRM), and the Agence Nationale de la Recherche (ANR-06-Physio-032-01 and ANR-09-BLAN-0121-01). This work was also supported by National Institutes of Health Grant HL63762 (to J. H.).
Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/3/4
Y1 - 2016/3/4
N2 - The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (α) chain of LRP1 mediates TGFβ-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (β) chain of LRP1 suffices to limit cholesterol accumulation in LRP1-/- cells. Through binding of Erk2 to the second of its carboxyl-terminal NPXY motifs, LRP1 β-chain positively regulates the expression of ATP binding cassette transporter A1 (ABCA1) and of neutral cholesterol ester hydrolase (NCEH1). These results highlight the unexpected functions of LRP1 and the canonical Wnt5a pathway and new therapeutic potential in cholesterol-associated disorders including cardiovascular diseases.
AB - The low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell surface receptor that protects from intracellular cholesterol accumulation. However, the underlying mechanisms are unknown. Here we show that the extracellular (α) chain of LRP1 mediates TGFβ-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic (β) chain of LRP1 suffices to limit cholesterol accumulation in LRP1-/- cells. Through binding of Erk2 to the second of its carboxyl-terminal NPXY motifs, LRP1 β-chain positively regulates the expression of ATP binding cassette transporter A1 (ABCA1) and of neutral cholesterol ester hydrolase (NCEH1). These results highlight the unexpected functions of LRP1 and the canonical Wnt5a pathway and new therapeutic potential in cholesterol-associated disorders including cardiovascular diseases.
UR - http://www.scopus.com/inward/record.url?scp=84964584286&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964584286&partnerID=8YFLogxK
U2 - 10.1074/jbc.M116.714485
DO - 10.1074/jbc.M116.714485
M3 - Article
C2 - 26792864
AN - SCOPUS:84964584286
SN - 0021-9258
VL - 291
SP - 5116
EP - 5127
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -