Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation

Zeina El Asmar; Jérome Terrand; Marion Jenty; Lionel Host; Mohamed Mlih; Aurélie Zerr; Hélène Justiniano; Rachel L. Matz; Christian Boudier; Estelle Scholler; Jean Marie Garnier; Diego Bertaccini; Danièle Thiersé; Christine Schaeffer; Alain Van Dorsselaer; Joachim Herz; Véronique Bruban; Philippe Boucher

doi:10.1074/jbc.M116.714485

Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation

Zeina El Asmar, Jérome Terrand, Marion Jenty, Lionel Host, Mohamed Mlih, Aurélie Zerr, Hélène Justiniano, Rachel L. Matz, Christian Boudier, Estelle Scholler, Jean Marie Garnier, Diego Bertaccini, Danièle Thiersé, Christine Schaeffer, Alain Van Dorsselaer, Joachim Herz, Véronique Bruban, Philippe Boucher

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5116-5127
Number of pages	12
Journal	Journal of Biological Chemistry
Volume	291
Issue number	10
DOIs	https://doi.org/10.1074/jbc.M116.714485
State	Published - Mar 4 2016

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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El Asmar, Z., Terrand, J., Jenty, M., Host, L., Mlih, M., Zerr, A., Justiniano, H., Matz, R. L., Boudier, C., Scholler, E., Garnier, J. M., Bertaccini, D., Thiersé, D., Schaeffer, C., Van Dorsselaer, A., Herz, J., Bruban, V., & Boucher, P. (2016). Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation. Journal of Biological Chemistry, 291(10), 5116-5127. https://doi.org/10.1074/jbc.M116.714485

El Asmar, Z, Terrand, J, Jenty, M, Host, L, Mlih, M, Zerr, A, Justiniano, H, Matz, RL, Boudier, C, Scholler, E, Garnier, JM, Bertaccini, D, Thiersé, D, Schaeffer, C, Van Dorsselaer, A, Herz, J, Bruban, V & Boucher, P 2016, 'Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation', Journal of Biological Chemistry, vol. 291, no. 10, pp. 5116-5127. https://doi.org/10.1074/jbc.M116.714485

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title = "Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation",

abstract = "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.",

author = "{El Asmar}, Zeina and J{\'e}rome Terrand and Marion Jenty and Lionel Host and Mohamed Mlih and Aur{\'e}lie Zerr and H{\'e}l{\`e}ne Justiniano and Matz, {Rachel L.} and Christian Boudier and Estelle Scholler and Garnier, {Jean Marie} and Diego Bertaccini and Dani{\`e}le Thiers{\'e} and Christine Schaeffer and {Van Dorsselaer}, Alain and Joachim Herz and V{\'e}ronique Bruban and Philippe Boucher",

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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

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.

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Convergent signaling pathways controlled by LRP1 (Receptor-related Protein 1) cytoplasmic and extracellular domains limit cellular cholesterol accumulation

Abstract

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