Apolipoprotein function

FIGURE 9-1. Lipoprotein structure. Lipoproteins are a diverse group of particles with varying size and density. They contain variable amounts of core cholesterol esters and triglycerides, and have varying numbers and types of surface apolipoproteins. The apolipoproteins function to direct the processing and removal of individual lipoprotein particles. (Reprinted from LipoScience, Inc. with permission.)... 

Interactions of apolipoproteins with PL are essential for the assembly of lipoproteins, stabilization of lipoprotein structures, and expression and modulation of apolipoprotein functions. The main experimental approaches for the study of apolipoprotein interactions with PL have used isolated, exchangeable apolipoproteins in conjunction with aggregated lipids dispersed in water or spread at the air-water interface. The aggregated lipid states include lipid monolayers, various types of liposomes (small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles), and emulsions. All these lipid systems consist of or include PL, especially PC. 

Narayanaswami, V., Ryan, R.O. 2000. Molecular basis of exchangeable apolipoprotein function. Biochim. Biophys. Acta 1483 15-36. 

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). 

The method utilizing ID NMR is simple and eonvenient. Henee the NMR method diseussed here ean be applied to the systematie investigation of the membrane irug inter-aetions, elosely related to the vital function in biomembranes. It is expected that the application can be extended to the lipid-peptide interaction and protein uptake. We are now applying the method to apolipoprotein binding with lipid bilayers and emulsions. Preferential protein binding sites in membranes can be specified by NMR on the molecular level. 

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. 

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. 

Narayanaswami, V., Maiorano, J. N., Dhanasekaran, P. et al. Helix orientation of the functional domains in apolipoprotein e in discoidal high density lipoprotein particles. /. Biol. Chem. 279 14273-14279, 2004. 

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. 

R15. Rosseneu, M., and Labeur, C., Apolipoprotein structure, function and measurement. Curr. Opin. Lipidol. 1, 508-513 (1990). 

In the review dealing with the proteins of plasma lipoproteins, Scanu and Ritter have produced a most lucid and detailed discussion of recent advances in this difficult field. An exciting account is given of the isolation of apolipoproteins, their chemical structure, and what is known of their biological functions lipoproteins relevant to patients with dyslipo-proteinemia are also described. 

Apoliprotein. Any of the protein constituents of lipoproteins, grouped by function in four classes A, B, C, and E (the former apolipoprotein [apo] D is now apo A-111). Apoptosis. Fragmentation of a cell into membrane-bound particles that are eliminated by phagocytosis. Programmed cell death. 

Bianco et al. [34] CNT-r proteins (fibrinogen, protein A, erythropoietin, and apolipoprotein) CNT-TEG-short protein complex quickly entered fibroblasts and other cells, sometimes migrated to their nuclei. Proteins executed their normal biological functions... 

Each class of lipoprotein has a specific function, determined by its point of synthesis, lipid composition, and apolipoprotein content. At least nine different apolipoproteins are found in the lipoproteins of human plasma (Table 21-3), distinguishable by their size, their reactions with specific antibodies, and their characteristic distribution in the lipoprotein classes. These protein components act as signals, targeting lipoproteins to specific tissues or activating enzymes that act on the lipoproteins. 

Apolipoprotein Molecular weight Lipoprotein association Function (if known)... 

The molecular basis for the association between apoE4 and Alzheimer s disease is not yet known. Speculation has focused on a possible role for apoE in stabilizing the cytoslceletal structure of neurons. The apoE2 and apoE3 proteins bind to a number of proteins associated with neuronal microtubules, whereas apoE4 does not. This may accelerate the death of neurons. Whatever the mechanism proves to be, these observations promise to expand our understanding of the biological functions of apolipoproteins. 

In adipose tissue, TAG is stored in the cytosol of the cells in a nearly anhydrous form. It serves as "depot fat," ready for mobilization when the body requires it for fuel. Little TAG is stored in the liver. Instead, most is exported, packaged with cholesteryl esters, cholesterol, phospholipid, and protein (apolipoprotein B-100, see p. 229) to form lipoprotein particles called very low density lipoproteins (VLDL). Nascent VLDL are secreted into the blood where they mature and function to deliver the endogenously-derived lipids to the peripheral tissues. [Note Recall that chylomicrons deliver primarily dietary (exogenously-derived) lipids.] Plasma lipoproteins are discussed in Chapter 18, p. 225. 

The plasma lipoproteins are spherical macromolecular complexes of lipids and specific proteins (apolipoproteins or apoproteins). The lipoprotein particles include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They differ in lipid and protein composition, size, and density (Figure 18.13). Lipoproteins function both to keep their component lipids soluble as they transport them in the plasma, and also to provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. In humans, the transport system is less perfect than in other animals and, as a result, humans experience a yradual deposition of lipid—especially cholesterol—in tissues. This is a potentially life-threat-en ng occurrence when the lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis). 

Apolipoproteins The apolipoproteins associated with lipoprotein particles have a number of diverse functions, such as providing recognition sites for cell-surface receptors, and serving as activators or coenzymes for enzymes involved in lipoprotein metabolism. Some of the apolipoproteins are required as essential structural components of the particles and cannot be removed (in fact, the particles cannot be produced without them), whereas others are transfered freely between lipoproteins. Apolipoproteins are divided by structure and function into five major classes, A through E, with most classes having subclasses, for example, apo A-l and apo C-ll. [Note Functions of all of the apolipoproteins are not yet known.]... 

Modification of nascent chylomicron particles The particle released by the intestinal mucosal cell is called a "nascent" chylomicron because it is functionally incomplete. When it reaches the plasma, the particle is rapidly modified, receiving apo E (which is recognized by hepatic receptors) and C apolipoproteins, The latter include apo C-ll, which is necessary for the activation of lipoprotein lipase, the enzyme that degrades the triacylglycerol contained in the chylomicron (see below). The source of these apolipoproteins is circulating HDL (see Figure 18.16). 

The plasma lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They function to keep lipids (primarily triacylglyc-erol and cholesteryl esters) soluble as they transport them between tissues. Lipoproteins are composed of a neutral lipid core (containing triacylglycerol, cholesteryl esters, or both) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified cholesterol. Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily, triacylglycerol) plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs, thus making the chylomicrons functional. Apo C-ll activates lipoprotein lipase, which degrades the... 

Chylomicrons are assembled in intestinal mucosal cells from dietary lipids (primarily triacylglycerol), plus additional lipids synthesized in these cells. Each nascent chylomicron particle has one molecule of apolipoprotein B-48 (apo B-48). They are released from the cells into the lymphatic system and travel to the blood, where they receive apo C-ll and apo E from HDLs. This makes the chylomicrons functional. 

Each apolipoprotein has one or more distinct functions. The apoB proteins probably stabilize the lipoprotein micelles. In addition, apoB-100 is essential to recognition of LDL by its receptors. The 79-residue apoC-II has a specific function of activating the lipoprotein lipase that hydrolyses the triacylglycerols of chylomicrons and VLDL. Lack of either C-II or the lipase results in a very high level of triacylglycerols in the blood.11... 

Apolipoprotein A-I is the primary protein component of HDL.23 2513 Most of the 243 residues consist of a nearly continuous amphipathic a helix with kinks at regularly spaced proline residues.26 28 Two disulfide-linked ApoA-I molecules may form a belt that encircles the discoid lipoprotein.2513 ApoA-II is the second major HDL protein, but no dearly specialized function has been identified.29 30 ApoA-I, II, and IV, apoC-I, II, and III, and apoE all have multiple repeats of 22 amino acids with sequences that suggest amphipathic helices. Tire 391-residue ApoA-IV has 13 tandem 22-residue repeats. Proline and glycine are present in intervening hinge regions.23 This may enable these proteins to spread over and penetrate the surfaces of the lipoprotein micelles. Most of these proteins are encoded by a related multigene family.7 303... 

---