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J Biol Chem. 2016 Mar 4;291(10):5116-27. doi: 10.1074/jbc.M116.714485. Epub 2016 Jan 19.

Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation.

Author information

1
From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
2
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM 964/CNRS UMR 7104, University of Strasbourg, 67401 Illkirch, France.
3
CNRS, UMR 7178, University of Strasbourg, 67087 Strasbourg, France, and.
4
Department of Molecular Genetics and Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, Texas 75390.
5
From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, veronique.bruban@unistra.fr.
6
From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, philippe.boucher@unistra.fr.

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.

KEYWORDS:

ABC transporter; Wnt pathway; atherosclerosis; cholesterol regulation; lipoprotein receptor-related protein 1 (LRP1); transgenic mice

PMID:
26792864
PMCID:
PMC4777846
DOI:
10.1074/jbc.M116.714485
[Indexed for MEDLINE]
Free PMC Article

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