LDL receptor-related protein

Chylomicron remnants are taken up by the liver by receptor-mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Uptake is mediated by a receptor specific for apo E (Figure 25-3), and both the LDL (apo B-lOO, E) receptor and the LRP (LDL receptor-related protein)... 

Kang, D.E., Pietrzik, C.U., Baum, L., et al. (2000) Modulation of amyloid beta-protein clearance and Alzheimer s disease susceptibility by the LDL receptor-related protein pathway. J. Clin. Invest., 106, 1159-1166. 

R. R., and Johnson, M.L. (2002) A Mutation in the LDL Receptor Related Protein 5 Gene Results in the Autosomal Dominant High Bone Mass Trait. American Journal of Human Genetics 70, 11-19. 

VanWesenbeeck, L., Cleiren, E., Gram, J., Beals, R.K., Benichou, 0., Scopelliti, D., Key, L., Renton, T., Bartels, C., Gong, Y., Warman, M.L., DeVernejonl, M-C., Bollerslev, J., and VanHnl, W. (2003) Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density. American Journal of Human Genetlcsll, 763-771. 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

M. Krieger and J. Herz, Structures and functions of multiligand lipoprotein receptors Macrophage scavenger receptors and LDL receptor-related protein (LRP), Annu. Rev. Biochem. 63 (1994) 601-637. 

U. Beiseigel, W. Weber, G. Ihrke, J. Herz and K.K. Stanley, The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein, Nature 341 (1989) 162-164. 

Weatherbee, S. D., Anderson, K. V. and Niswander, L. A. (2006) LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 133,4993-5000. 

Yepes M, Sandkvist M, Moore EG, Bugge TH, Strickland DK, Lawrence DA (2003) Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 112 1533-1540... 

Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG. Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. Mol Biol Cell 2001 12(5) 1467-1479. 

Cholesterol is absorbed from the intestine and transported to the liver by chylomicron remnants, which are taken up by the low-density lipoprotein (LDL)-receptor-related protein (LRP). 

Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer s amyloid- 3 1 0 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106 1489-1499. 

LRP LDL-receptor-related protein NAME nitric oxide s mthase inhibitor... 

Hussaini IM, LaMarre J, Lysiak JJ, et al. Transcriptional regulation of LDL receptor-related protein by IFN-y and the antagonistic activity of TGF-p(l) in the RAW 264.7 macrophage-like cell line. J Leukoc Biol 1996 59 733-9. 

Llorente-Cortes V, Badimon L (2005) LDL receptor-related protein and the vascular wall implications for atherothrombosis. Arterioscler Thromb Vase Biol 25 497-504... 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

Chylomicrons, large triglyceride-rich particles containing apolipoprotein B-48, B-lOO, and E, are formed from dietary fat solubilized by bile salts in intestinal mucosal cells (Fig. 21-2). Chylomicrons normally are not present in the plasma after a fast of 12 to 14 hours and are catabolized by lipoprotein lipase (LPL), which is activated by apolipoprotein C-II, in the vascular endothelium and hepatic lipase to form chylomicron remnants. The remnants that contain apolipoprotein E (see Fig. 21-2) are taken up by the remnant receptor, which may be an LDL-receptor-related protein, in the liver. Free cholesterol is liberated intracellularly after attachment to the remnant receptor. Chylomicrons also function to deliver dietary triglyceride to skeletal muscle and adipose tissue. During the catabolism of nascent chylomicrons to remnants, triglyceride is converted to free fatty acids and apolipoproteins A-I, A-II, A-IV (free in plasma), C-I, C-II, and... 

Receptors Frizzled (Fz) with seven transmembrane a helices associated membrane-bound LDL receptor-related protein (Lrp) required for receptor activity Signal transduction Assembly of multiprotein complex at membrane that inhibits the proteasome-mediated proteolysis of cytosolic p-catenin transcription factor, resulting in its accumulation... 

Fig. 3. Synthesis, secretion, and transport of lipoprotein lipase (LPL) from the adipocyte to the vascular endothelial surface of adipose tissue. Degradative pathways from the Golgi compartment and cell surface are illustrated. ER, endoplasmic reticulum RAP, receptor-associated protein LRP, LDL receptor-related protein.

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

Both the so-called LDL receptor-related protein (R in Fig. 1, and Section 3.1) and the LDL receptor (a in Fig. 1, and Section 2) mediate their removal via recognition of apo E. The apo B48, which resides on chylomicrons throughout their life span, is not recognized by these receptors. 

FIGURE 35-1 The miyor pathwi s involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. Remnant receptors include die LDL receptor-related protein (LRP), LDL, and perhaps other receptors. FFA released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose tissue. FFA, free fatty acid HL, hepatic lipase IDL, intermediate-density lipoproteins LDL, low-density lipoproteins LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

ApoE Liver 34,145 Chylomicron remnants, VLDL, IDL, HDL Ligand for binding of several lipoproteins to the LDL receptor, to the LDL receptor-related protein (LRP) and possibly to a separate apo-E receptor. 

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