Apolipoprotein receptor

Apolipoproteins may interact with specific receptors, either to initiate uptake of a particle (e.g., apoE in remnant lipoproteins, apoB in LDL) or to inhibit uptake (e.g., apoC appears to inhibit hepatic uptake of triglyceride-rich apoE-containing particles). Apolipoprotein-receptor interactions are considered when the individual apolipoprotein is discussed. 

Inhibitory effects of high concentrations of LDL (2000 pg/ml) on endothelium-dependent arterial relaxation have been reported by Andrews et al. [119]. These authors suggested that the effects are mediated by an apolipoprotein receptor mechanism involving native LDL. 

J.E. Oram, R.M. Lawn, M.R. Garvin, and D.P. Wade, ABCAl is the cAMP-in-ducible apolipoprotein receptor that mediates cholesterol secretion from macrophages, J. Biol. Chem., 2000, 275, 34508-34511. 

Fourth, various modifications of a cellular pathway of CE metabolism involving plasma lipoprotein CE, apolipoprotein receptors associated with the cell surface, a lysosomal CEH, an intracellular ACAT, and a cytoplasmic, neutral CEH, can contribute to several cell functions. These functions include the synthesis of cell membranes, steroid hormones, or bile acids as well as the specialized scavenger functions of macrophages. 

Proteins embedded in the shell of lipoproteins. They serve as scaffold for assembly of the lipoprotein particle in the endoplasmic reticulum. In addition, they control metabolism of lipoproteins in the circulation by interaction with enzymes such as lipases. Finally, apolipoproteins determine cellular uptake of the particles by interaction with specific lipoprotein receptors expressed on the surface of target cells. 

Figure 25-3. Metabolic fate of chylomicrons. (A, apolipoprotein A B-48, apolipoprotein B-48 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylgiycerol C, cholesterol and cholesteryl ester P, phospholipid HL, hepatic lipase LRP, LDL receptor-reiated protein.) Only the predominant lipids are shown.

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

In contrast to MDA and hydroxynonenai, other aldehyde products of lipid peroxidation are hydrophobic and remain closely associated with LDL to accumulate to mil-limolar concentrations. Aldehydes at these elevated levels react with the protein portion of the LDL molecule, apolipoprotein B (apoB). Accumulated aldehydes bind the free amino groups from lysine residues in addition to other functional groups (-OH, -SH) on the apoB polypeptide. Consequently, the protein takes on a net negative charge and complete structural rearrangement results in the formation of ox-LDL. ox-LDL is no longer recognized by the LDL receptor, and has several pro-inflammatory properties (discussed below). 

Fig. 9-4). Very low-density lipoprotein particles are released into the circulation where they acquire apolipoprotein E and apolipoprotein C-II from HDL. Very-low density lipoprotein loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. Intermediate-density lipoprotein can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. Low-density lipoprotein particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with apolipoprotein B-100. They can also be taken up by extra-hepatic tissues or enter the arterial wall, contributing to atherogenesis.4,6... 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Fibrates work by reducing apolipoproteins B, C-III (an inhibitor of LPL), and E, and increasing apolipoproteins A-I and A-II through activation of peroxisome proliferator-activated receptors-alpha (PPAR-a), a nuclear receptor involved in cellular function. The changes in these apolipoproteins result in a reduction in triglyceride-rich lipoproteins (VLDL and IDL) and an increase in HDL. 

Dawson TC, Kuziel WA, Osahar TA, Maeda N. Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 1999 143(1) 205—211. 

It needs to be noted that apart from expression of lipoprotein receptors, RPE itself expresses several apolipoproteins (Bartl et al., 2001 Ishida et al., 2004 Li et al., 2006 Malek et al., 2003 Tserentsoodol et al., 2006a). So far, six apolipoproteins have been identified as being expressed by the RPE, namely, apolipoprotein A-I (ApoA-I), ApoB, ApoC-I, ApoC-II, ApoE, and ApoJ (clusterin) (Bailey et al., 2004 Bartl et al., 2001 Ishida et al., 2004 Li et al., 2006 Malek et al., 2003 Tserentsoodol et al., 2006a). In addition to their functions as lipid transporters and receptor ligands, apo-lipoproteins can act as modulators of several enzymes. The basic characteristics of apo-lipoproteins expressed by the RPE are described below. 

Bultel-Brienne, S, Lestavel, S, Pilon, A, Laffont, I, Tailleux, A, Fruchart, JC, Siest, G, and Clavey, V, 2002. Lipid free apolipoprotein E binds to the class B type I scavenger receptor I (SR-BI) and enhances cholesteryl ester uptake from hpoproteins. J Biol Chem 277, 36092-36099. 

Lorenzi, I, von Eckardstein, A, Cavelier, C, Radosavljevic, S, and Rohrer, L, 2008. Apolipoprotein A-I but not high-density lipoproteins are internalised by RAW macrophages Roles of ATP-binding cassette transporter A1 and scavenger receptor BI. JMolMed 86, 171-183. 

Marz W, Baumstark M, Scharnagl H, Ruzicka V, Buxbaum S, Herwig J, et al. Accumulation of small dense low density lipoproteins in a homozygous patient with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor. J Clin Invest 1993 92 2922-2933. 

Two important cis-acting elements in the ALDH2 promoter have been studied. A site located from 79 to 116 bp upstream of the ATG initiating translation is bound by nuclear factor(s) present in all cells tested the CCAAT box in this region is important for transcriptional activity, and appears to be bound primarily by the transcription factor NF-Y/CP1 [46]. There is a site, approximately 300 bp upstream of the ATG, at which HNF-4 and retinoid X receptors can bind, as can the apolipoproteins regulatory protein (ARP-1) [47, 48]. Transcription from this promoter can be activated by HNF-4 and RXRs [47, 48]. 

Tangirala RK, Rubin EM, Palinski W (1995) Quantitation of atherosclerosis in murine models correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J Lipid Res 36 2320-2328... 

Based on well established silica chemistry, the surface of silica nanomaterials can be modified to introduce a variety of functionalizations [3, 11, 118]. The toxicity of surface-modified nanomaterials is largely determined by their surface functional groups. As an example, Kreuter reported that an apolipoprotein coating on silica nanoparticles aided their endocytosis in brain capillaries through the LDL-receptor [122-124]. Overall, silica nanomaterials are low-toxicity materials, although their toxicity can be altered by surface modifications. 

The biological half-life in plasma of Lp(a) equals that of LDL (K37). However, LDL-receptor activity does not fully account for the main catabolic pathway of Lp(a) (A13, A15, K19, Ml, M10). Only a modest uptake, if any, of Lp(a) by the LDL receptors has been reported (F12, H21, K37, S36). Moreover, this uptake can possibly be influenced by the presence of other apolipoproteins as apo-E (B4, H37, K20). 

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