Apoproteins, plasma lipoproteins

Research on plasma lipoproteins has entered a highly productive period during which major advances have been made from both the conceptual and technological standpoints. The information gained on lipoprotein apoproteins has particular relevance, especially in terms of pri-... 

E4. Eisenberg, S., Bilheimer, D. W., and Levy, R. I., The metabolism of very low density lipoproteins proteins. II. Studies on the transfer of apoproteins between plasma lipoproteins. Biochim. Biophys. Acta 280, 94-104 (1972). 

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). 

The plasma lipoproteins are made mainly in the liver and intestine. In the rat, approximately 80% of the plasma apoproteins originate from the liver the rest are derived from the intestine. The components of chylomicrons, including apoproteins A-I, A-IV, and B-48 phospholipid cholesterol cholesteryl ester and triacylglycerols, are products of the intestinal cells. Chylomicrons are secreted into lymphatic capillaries, which eventually enter the bloodstream. The liver is the major source of VLDLs and HDLs. 

The plasma lipoproteins contain eight major apoproteins, the structure and function of which have recently been reviewed (5). Briefly, the primary amino acid sequence is known for five of these apoproteins. ApoB, a highly hydrophobic protein, is found in chylomicrons, VLDL and LDL. It is the major polypeptide in LDL and has been shown to be responsible, in part, for the recognition of LDL by its receptor in cultured human fibroblasts (7,10). The major polypeptides of HDL are apoA-I and apoA-II apoA-l activates lecithin cholesterol acyl transferase. In addition, studies on the cellular level suggest that apoA-I may regulate the content of the lipids in the cell membrane (8). 

The general structure of lipoproteins is shown schematically in Figure 3. The core of the lipoprotein contains the more hydrophobic lipids namely cholesterol ester (CE) and triglyceride (TG) and is surrounded by a surface monolayer consisting of the more polar phospholipid (PL) and free cholesterol (FC). Apoproteins are associated with the lipoprotein surface. The proportional composition of human plasma lipoproteins is given in Table 7. 

M15. Mahley, R. W., Innerarity, T. L., Weisgraber, K. H., and Oh, S. Y., Altered metabolism (in vivo and in vitro) of plasma lipoproteins after selective chemical modification of lysine residues of the apoproteins. J. Clin. Invest. 64, 743-750 (1979). 

Wll. Weisgraber, K. H., and Mahley, R. W., Apoprotein (E-A-II) complex of human plasma lipoproteins. I. Characterization of this mixed disulfide and its identification in a high density lipoprotein subfraction. J. Biol. Chem. 253, 6281-6288 (1978). 

Calvert, G.D., Abbey, M. Plasma lipoproteins apoproteins and proteins concerned with lipid metabohsm. Adv. Clrn. Chem. 1985 24 218-298... 

About 80% of the cholesterol synthesized in the liver is converted into bile salts. The remainder of the cholesterol, triacylglycerols, other lipids, and hydrophobic substances (including xenobiotics) are transported to other tissues throughout the body by plasma lipoproteins. These lipoproteins, which are classified according to density, consist of apoproteins (also made by the liver) and various combinations of fat and fat-soluble compounds. The liver also stores vitamins, especially vitamin A but also vitamins D, E and K, as well as vitamin B12, in fatstoring Ito cells, located between endothelial cells and hepatocytes. 

Although the term lipoprotein can describe any protein that is covalently linked to lipid groups (e.g., fatty acids or prenyl groups), it is most often used for a group of molecular complexes found in the blood plasma of mammals (especially humans). Plasma lipoproteins transport lipid molecules (triacylglycerols, phospholipids, and cholesterol) through the bloodstream from one organ to another. Lipoproteins also contain several types of lipid-soluble antioxidant molecules (e.g., a-tocopherol and several carotenoids). (The function of antioxidants, substances that protect biomolecules from free radicals, is described in Chapter 10.) The protein components of lipoproteins are called apolipoproteins or apoproteins. 

Alexander, C.A., Hamilton, R.L., Havel, R.J. 1976. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J. Cell Biol. 69 241-263. 

Cholesterol travels in the bloodstream via lipoprotein complexes called Chylomicrons, VLDL, IDL, LDL, and HDL. Of the five lipoprotein classes, LDL is by far the richest in cholesterol. Cholesterol in plasma lipoproteins exists both as the free sterol and esterified at its hydroxyl position with a long-chain fatty acid, usually unsaturated (see also Table 18.1). The LDL particle contains a single molecule of apoprotein B-lOO (Mr = 513,000) as its primary protein component. Because cholesterol biosynthesis is confined primarily to the liver with some occurring also in intestine, LDL plays an important role in delivering cholesterol to other tissues. Cholesterol esters are too hydrophobic to traverse cell membranes by themselves and must be transported into cells via specialized LDL receptors. 

Mahley, R. W., and K. S. Holcombe. 1977. Alterations of the plasma lipoproteins and apoproteins following cholesterol feeding in rats. Journal of Lipid Research 18 314—324. 

Lipoproteins are macromolecular assemblies that contain proteins and lipids, including free and esterified cholesterol, triglycerides, and phospholipids. The protein components, known as apoUpoprotems, provide structural stability to the lipoproteins, and also may function as ligands in hpoprotein-receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism. In aU Upoprotems, the most water-insoluble lipids (cholesteryl esters and triglycerides) are core components, and the more polar, water-soluble components (apoproteins, phospholipids, and unesterified cholesterol) are located on the surface. The major classes of lipoproteins and their properties are presented in Table 35-1. Table 35-2 describes apoproteins that have well-defined roles in plasma lipoprotein metabolism. 

Apart from their operational distinction on the basis of density and lipid composition the plasma lipoprotein classes are also distinguished by the nature of the polypeptides present. The apoprotein species have been characterized and designated family names from A to H. The human plasma lipoprotein apoprotein distribution is shown in Table 12.3. Although the distribution, interchange and metabolism of lipoprotein apoproteins is extremely complicated some overall aspects of the dynamic situation can be discerned (see Schaefer etal, 1978). For example, the apoprotein content of newly synthesized VLDL and chylomicrons changes drastically as these lipoproteins enter the circulation and interact with the other lipoproteins present. Both... 

Table 12.3 Apoprotein distribution in human plasma lipoprotein classes (data taken from Smith et al., 1978)...

Plasma contains an apoprotein which combines with lipids in the liver to form plasma lipoproteins [301]. Rats treated with orotic acid did produce this apoprotein but the formation of plasma lipoproteins from apoprotein... 

Ishikawa, T. and Fidge, N. (1979) Changes in the concentration of plasma lipoproteins and apoproteins follorving the administration of I riton WR-1339 to rats. Journal of Lipid lieseanh, 20, 294-264. 

Plasma lipoproteins (LPs) are soluble aggregates of lipids and proteins that deliver hydrophobic, water-insoluble lipids (triglycerides and cholesteryl esters) from the liver and intestine to other tissues in the body for storage or utilization as an energy source [60]. All LP particles have a common structure of a neutral lipid core surrounded by a surface monolayer of amphipathic lipids (phospholipids and unesterified cholesterol) and some specific apoproteins (Fig. 14). The LPs are usually classified according to density, from very low-density lipoprotein (VLDL) to high-density lipoprotein (HDL). The size of LPs varies from 5-12 nm for HDL to 30-80 nm for VLDL. 

Four main classes of plasma lipoprotein can be recognized from their densities and electrophoretic mobilities. They are all large complexes that contain triglycerides, phospholipids, cholesterol, cholesteryl esters and protein in varying proportions (Table 25.4) and consist of a hydrophobic core surrounded by a shell of proteins and phospholipids. The proteins are known as apolipoproteins or apoproteins. These are formed in the liver and small intestine and are of many different kinds. Some of them act as enzyme activators. 

Plasma lipoproteins are macromolecular complexes of such chemically diverse substances as proteins, various kinds of lipids and, to minor proportions, carbohydrates. They serve primarily as transport vehicles for lipids in the aqueous environment of blood and lymph and represent an enormously broad spectrum of compostions and particle sizes. Traditionally lipoproteins are classified upon the operationally useful characteristic of buoyant density initiated by the ultracentrifugal separation studies by DeLalla and Gofman (1954) (Table 1). A biochemically more specific nomenclature was pioneered by Alaupovic (1972), whereby lipoprotein families are defined by their specific apolipoproteins. This concept of lipoprotein families has proven particularly useful in relating certain biochemical functions of individual lipoprotein classes to their apoproteins. 

The cammon features of plasma lipoprotein structure are shown in Fig. 2. The interior of the lipoproteins contains the neutral lipids, cholesteryl ester and triglyceride. The exterior surface is a monomolecular film of specific proteins, termed apolipopro-teins, and the polar lipids, phosphatidylcholine and cholesterol. One possible arrangement (Edelstein et al., 1979) of the phosphatidylcholine, cholesterol and apolipoprotein A-1 (apoA-1) in HDL the most abundant of the plasma lipoproteins, is illustrated schematically in Fig. 3. In this model, there are no lipid domains in the surface of HDL. The phospholipid molecules are widely dispersed so that intermolecular associations can involve only apoprotein lipid and apoprotein apoprotein interactions. By contrast, with increasing size and a greater proportion of hydrophobic core volume, the structure of the larger lipoproteins more closely re-... 

Table 6. Apoprotein Composition of Human Plasma Lipoproteins...

Lipid transport diseases as a result of genetic defects resulting either in faulty apoproteins or their cellular receptors, the circulating concentrations of lipoproteins can be abnormally high, or, more rarely, low. High concentrations of plasma lipoproteins are, in turn, associated with a number of diseases including diabetes and ischaemic heart disease... 

Becker, N., Illingsworth, R., Alaupovic, P., Connor, W. E., Sundberg, E. E., Effects of saturated, monounsaturated, and w-6 polyunsaturated fatty acids on plasma lipids, lipoproteins and apoproteins in humans, Am J Clin Nutr, 37, 355, 1983... 

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