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.
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Zeina
authors.initials: Z
authors.lastname: El Asmar
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Terrand
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Jenty
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Host
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mlih
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Zerr
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Justiniano
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Matz
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Boudier
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Scholler
authors.affiliation: IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM 964/CNRS UMR 7104, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Garnier
authors.affiliation: CNRS, UMR 7178, University of Strasbourg, 67087 Strasbourg, France, and.
authors.forename: Diego
authors.initials: D
authors.lastname: Bertaccini
authors.affiliation: CNRS, UMR 7178, University of Strasbourg, 67087 Strasbourg, France, and.
authors.forename: Danièle
authors.initials: D
authors.lastname: Thiersé
authors.affiliation: CNRS, UMR 7178, University of Strasbourg, 67087 Strasbourg, France, and.
authors.forename: Christine
authors.initials: C
authors.lastname: Schaeffer
authors.affiliation: CNRS, UMR 7178, University of Strasbourg, 67087 Strasbourg, France, and.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Department of Molecular Genetics and Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, veronique.bruban@unistra.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bruban
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, philippe.boucher@unistra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Boucher
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011973:Receptors, LDL / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019950:Mitogen-Activated Protein Kinase 1; D011973:Receptors, LDL; D002787:Sterol Esterase; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C577833:Abca1 protein, mouse; C486645:Lrp1 protein, mouse; C438615:Wnt5a protein, mouse; C514712:Nceh1 protein, mouse
keywords: ABC transporter; Wnt pathway; atherosclerosis; cholesterol regulation; lipoprotein receptor-related protein 1 (LRP1); transgenic mice