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

作者：Zeina El Asmar, Jérôme Terrand, Marion Jenty, Lionel Host, Mohamed Mlih, A. Zerr, Hélène Justiniano, Rachel L. Matz, Christian Boudier, Estelle Scholler, Jean‐Marie Garnier, Diego Bertaccini, Danièle Thiersé, Christine Schaeffer‐Reiss, Alain Van Dorsselaer, Joachim Herz, Véronique Bruban, Philippe Boucher · 发表于：Journal of Biological Chemistry · 年份：2016 · DOI：10.1074/jbc.m116.714485 · 被引用次数：39 · 研究领域：Cholesterol and Lipid Metabolism、Cellular transport and secretion、Caveolin-1 and cellular processes

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.