Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation
Convergent Signaling Pathways Controlled by LRP1 (Receptor-related Protein 1) Cytoplasmic and Extracellular Domains Limit Cellular Cholesterol Accumulation
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DOI：
10.1074/jbc.m116.714485
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发表时间：
2016-03-04
影响因子：
4.8
通讯作者：
Boucher, Philippe
中科院分区：
文献类型：
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作者：
El Asmar, Zeina;Terrand, Jerome;Boucher, Philippe
低密度脂蛋白受体相关蛋白1 （LRP1）是一种普遍表达的细胞表面受体，可防止细胞内胆固醇积累。然而，其潜在机制尚不清楚。本研究表明，LRP1的细胞外链介导tgf诱导的Wnt5a增强，通过抑制胆固醇生物合成和促进胆固醇输出来限制细胞内胆固醇积累。此外，我们证明了LRP1的细胞质链足以限制胆固醇在LRP1（-/-）细胞中的积累。LRP1 -链通过Erk2与第二个羧基端NPXY基序结合，正向调节ATP结合盒转运体A1 （ABCA1）和中性胆固醇酯水解酶（NCEH1）的表达。这些结果突出了LRP1和典型Wnt5a通路的意想不到的功能，以及在胆固醇相关疾病（包括心血管疾病）中的新的治疗潜力。
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 () chain of LRP1 mediates TGF-induced enhancement of Wnt5a, which limits intracellular cholesterol accumulation by inhibiting cholesterol biosynthesis and by promoting cholesterol export. Moreover, we demonstrate that the cytoplasmic () 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 -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.