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First published online August 24, 2007
doi: 10.1242/10.1242/dev.004408

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Lipoproteins and their receptors in embryonic development: more than cholesterol clearance

¹ Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany.
² Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany.

View larger version (59K): [in this window] [in a new window]   Fig. 1. The LDL receptor family. The structural organization of members of the LDL receptor family. Their extracellular domains contain clusters of complement-type repeats that are the site of ligand binding, and also ß-propellers, which are essential for the pH-dependent release of ligands in endosomes. The cytoplasmic tails harbor recognition sites for adaptor proteins that are involved in protein trafficking and signal transduction. All ectodomains share significant sequence similarity in line with the ability of the receptors to bind apolipoproteins. By contrast, the cytoplasmic domains are unique, indicating distinct cellular fates for ligands internalized by individual receptors. Receptors on the left are considered to be core members of the protein family as their extracellular domains are built from a unifying module of amino-terminal complement-type repeats, followed by a carboxyl-terminal cluster of ß-propellers and epidermal growth factor-type repeats. This module can exist in single (e.g. LDLR) or multiple (e.g. LRP2) copies in the receptors. Receptors on the right are more distantly related, as the module is inverted (LRP5/6) or combined with motifs that are not seen in the other receptors (e.g. SORLA). APOER2, apolipoprotein E receptor 2; Ce, C. elegans; LDLR, low-density lipoprotein receptor; LRP, LDL receptor-related protein; MEGF7, multiple epidermal growth factor-type repeat containing protein 7; RME-2, receptor-mediated endocytosis-2; SORLA, sortilin-related receptor with A-type repeats; VLDLR, very low-density lipoprotein receptor.

View larger version (63K): [in this window] [in a new window]   Fig. 2. Lipoprotein receptors mediate uptake of lipoprotein-bound cholesterol. (A) Vertebrate lipoproteins are taken up by the LDL receptor via binding of apolipoproteins B or E present in the shell of the lipoprotein particle. Following endocytosis, the receptor discharges the lipoprotein particle in endosomes before recycling back to the cell surface. Internalized apolipoproteins are degraded in lysosomes, while cholesterol enters the cellular membrane pool via the endoplasmic reticulum (ER) or is converted into steroid hormones in mitochondria or is stored as cholesterol esters in cytoplasmic lipid droplets. The exit of cholesterol from lysosomes requires the activity of Niemann-Pick type C1 (NPC1), an integral membrane protein that acts as transporter for sterols. (B) C. elegans LRP-1 (Ce-LRP-1) also mediates the endocytic uptake of cholesterol-rich lipoproteins. Following release from endocytic compartments, cholesterol is converted into the steroid hormone gamravali, which blocks nuclear hormone receptor DAF-12-dependent induction of larval growth arrest. PM, plasma membrane.

View larger version (36K): [in this window] [in a new window]   Fig. 3. Lipoprotein receptors mediate uptake of steroid hormones bound to carrier proteins. In the circulation, androgens are solubilized by the sex hormone binding globulin (SHBG). Cell-type-specific uptake of SHBG-bound androgens involves the recognition of SHBG by LRP2 (megalin), followed by receptor-mediated endocytosis. In a process that parallels endocytic uptake of cholesterol in lipoproteins (see Fig. 2A), the protein moiety (here SHBG) is degraded in lysosomes, while the steroid enters the cytoplasm to exert its action (the induction of nuclear androgen receptors). Similar hormone-uptake pathways have been documented for SHBG-coupled estrogens and vitamin D binding protein-bound 25-hydroxyvitamin D3. PM, plasma membrane.

View larger version (30K): [in this window] [in a new window]   Fig. 4. Roles for lipoprotein association in morphogen signaling. (A) Heteromeric receptor complex formation between Frizzled and LRPs (e.g. LRP1, Arrow/LRP5/6) via simultaneous binding of Wnt ligands and apoproteins in lipoprotein particle may affect canonical Wnt signaling pathways. (B) Binding of Hh-modified lipoproteins to Patched and to LRPs may control Hh signaling directly or via cellular uptake of sterols with regulatory function. Extrac., extracellular; Intrac., intracellular; PM, plasma membrane. TCF, T cell factor.

View larger version (83K): [in this window] [in a new window]   Fig. 5. Sterol derivatives in hedgehog signaling. (A) The hedgehog (Hh) signaling pathway. Hh precursors undergo autocatalytic cleavage to generate a biologically active amino-terminal peptide covalently modified by cholesterol (HhN). Following release from cells, HhN acts on Patched to relieve Smoothened (SMO) repression, leading to the activation of the Gli family of transcription factors. (B) Oxysterols may positively regulate Hh signaling, either via repression of Patched (solid line) or the activation of SMO through as yet unknown mechanisms (dashed line). (C) Vitamin D metabolites negatively regulate SMO. Patched-expressing cells secrete a SMO inhibitor derived from 7-dehydrocholesterol that associates with lipoproteins (solid lines; right panel). In addition to locally synthesized sterols, exogenously derived vitamin D3 metabolites might also have the potential to affect SMO activity (left panel). These metabolites may enter cells either packaged in lipoprotein particles or complexed with vitamin D binding protein (DBP) via LRPs (dotted lines). Extrac., extracellular; Intrac., intracellular; PM, plasma membrane.

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