Lipoprotein Class

Lipoprotein Class Density (g/mL) Diameter (nm) Composition % dry weight) ... 

HDL and VLDL are assembled primarily in the endoplasmic reticulum of the liver (with smaller amounts produced in the intestine), whereas chylomicrons form in the intestine. LDL is not synthesized directly, but is made from VLDL. LDL appears to be the major circulatory complex for cholesterol and cholesterol esters. The primary task of chylomicrons is to transport triacylglycerols. Despite all this, it is extremely important to note that each of these lipoprotein classes contains some of each type of lipid. The relative amounts of HDL and LDL are important in the disposition of cholesterol in the body and in the development of arterial plaques (Figure 25.36). The structures of the various... 

In humans, CETP and PLTP are directly involved in the transfer of lipids between different lipoprotein classes. Through their action, these lipid transfer proteins have major effects on the concentration and composition of HDL. This section further describes the physiological function of CETP and PLTP in humans. 

Lipoprotein fraction containing triglycerides and to a lesser degree cholesterol. VLDL is produced by the liver. The main structural protein connected to this lipoprotein class is apolipoprotein B. 

Lp(a) measurements have found a wide range of applications since most of the structure, physiology, and genetics of this unusual lipoprotein class were unraveled (S14). 

Lipoprotein class Lipid components Main apoprotein components Enzymes present Role... 

Method of Separating Chylomicrons and the Various Lipoprotein Classes BY Sequential Flotation in the Ultracentripuge (All Run at 15°C)... 

Each of the major lipoprotein classes is abnormal by several criteria (F6, G13, N5). The electrophoretic mobility of the patients VLDL is that of a j8-lipoprotein rather than a pre-j8-lipoprotein (G12). Such an abnormality has been attributed to reduced levels of one or more of the VLDL peptides (G12). 

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. 

The structures of the various lipoproteins appear to be similar (figs. 20.11 and 20.12). Each of the lipoprotein classes contains a neutral lipid core composed of triacylglycerol and/or cholesteryl ester. Around this core is a coat of protein, phospholipid, and cholesterol, with the polar portions oriented toward the surface of the lipoprotein and the hydro-phobic parts associated with the neutral lipid core. The hydrophilic surface interacts with water in plasma, promoting the solubility of the lipoprotein. 

Properties of the Apoproteins of the Major Human Lipoprotein Classes... 

Plasma Lipoproteins. The plasma lipids are transported by four major lipoprotein classes. The plasma lipoproteins are synthesized and secreted only in the intestine and liver. Chylomicrons, the richest in triglyceride, are synthesized in the small intestine and transport dietary (exogenous) triglyceride and cholesterol. Very low density (prebeta) lipoproteins (VLDL)... 

Plasma lipoproteins are generally classified by their density and separation achieved with ultracentrifugation. According to this density-based classification system, the major lipoprotein classes are chylomicrons (CH), very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). 

The metabolism of HDL is less well defined than that of the other lipoprotein classes. Reasons for this include the heterogeneous nature of HDL and the interchange of both lipid and protein components between HDL and other lipoproteins. Furthermore, HDL are not removed from the circulation, because whole particles and their different components have different metabolic fates. 

Lipoproteins interact with enzymes (e.g., lecithin cholesterol acyltrans-ferase, or lipases), with lipid transfer proteins, or with receptors on cell surfaces. The composition of a lipoprotein class depends upon the results of these kinds of interactions. Ultracentrifugation itself may result in minor changes in lipoprotein composition (see Sections 6 and 6.1). 

In normolipidemic subjects, apoE is found not only in HDLc-like particles but also in two other fractions associated with triglyceride-rich lipoproteins. These are VLDL, and a lipoprotein class intermediate in size between VLDL and LDL (G3). The latter may be the normal counterpart of the (3-VLDL which accumulates in Type III hyperlipoproteinemia and in cholesterol-fed animals. 

Several types of proteins are associated with lipoproteins. These are termed apolipoproteins, or simply apoproteins. Table 19.2 shows the various apolipo-proteins (Apos), their chemical properties and occurrence, and their function, which is discussed later. Note that the A apoproteins are found largely in HDL, the B-100 is found largely in LDL, VLDL, and IDL, and C apoproteins are largely seen in chylomicrons. Nevertheless, there is a large degree of apoprotein overlap among the various lipoprotein classes. 

Cells need cholesterol to survive. Cells can either synthesize cholesterol de novo or obtain it from exogenous sources, such as lipoproteins present in the circulation (see Table 14-1 and Rader and Hobbs, 2005, for review). All of the lipoprotein classes contain phospholipids, es-terified and unesterified cholesterol, and triglycerides to varying degrees. LDL are the most abundant lipoproteins in humans. They are... 

Human lipoproteins exist in several sizes and densities with differing lipid to protein ratios. These various lipoproteins have different origins in the body, different destinations and different functions (10). Thus, chylomicrons are extremely large low density particles formed in the intestine and designed to deliver dietary fat to adipose tissue. Very low density lipoproteins (VLDL), on the other hand, are smaller, more dense particles designed to deliver lipids from the liver to adipose and other tissues. Low density lipoproteins (LDL), formed from VLDL or produced in the liver or intestine deliver cholesterol to peripheral tissue, while high density lipoproteins (HDL) function to return cholesterol from peripheral tissues to the liver for catabolism. There is a complex exchange of lipids and apoproteins between the lipoprotein classes. 

Although apoE was recognized first as a component of VLDLs (Shore and Shore, 1973 Shelburne and Quarfordt, 1974 Utermann, 1975 Kane et al., 1975), it has been demonstrated to be present in most other lipoprotein classes as well. In addition to occurring in the other triglyceride-rich lipoproteins, chylomicrons and their remnants, and the intermediate-density lipoproteins (IDEs), apoE is present in a subclass of the cholesterol-rich high-density lipoproteins (HDLs), referred to as HDL-with apoE (Mahley, 1978). By use of SDS-PAGE (Fig. 6), the Mr 34,200 apoE is easily distinguished from the other common apolipoproteins that also are present in the various human lipoprotein classes. 

Fig. 6. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of various human lipoprotein classes. The apolipoprotein components of the major lipoprotein classes were separated by SDS-PAGE on a 10% acrylamide gel in the absence of reducing agents. From Mahley and Innerarity (1983), with permission from Elsevier Science Publishers BV.

An additional feature of cholesterol/fat-fed animal models is the accumulation of HDL-with apoE. In several species, including dogs (Mahley el ai, 1974 Mahley and Weisgraber, 1983), rats (Mahley and Holcombe, 1977 Weisgraber and Mahley, 1983), pigs (Mahley et ai, 1975), and mice (de Silva et ai, 1992), the HDL-with apoE is a prominent lipoprotein class that extends into the lower density ranges overlapping in its density distribution with LDLs. The HDL-with apoE in these spe-... 

Chylomicrons are synthesized in the intestine and transport dietary triglycerides and cholesterol. While circulating, the core triglycerides in these particles are hydrolyzed by lipoprotein lipase, which results in the production of a cholesterol-enriched remnant particle. When synthesized and initially released by the intestine, chylomicrons contain essentially no apoE, but as they circulate and are processed to remnants, the particles acquire apoE from other lipoprotein classes. This results in a shift of the distribution of apoE in plasma to the triglyceride-rich remnants in the absorptive state (Blum, 1982). 

In addition, in species with high concentrations of HDL-with apoE, it has been postulated that this lipoprotein class serves to transport excess cholesterol from peripheral cells to the liver for elimination from the body (Mahley et al, 1980). This transport process is referred to as the reverse cholesterol transport process (Glomset, 1968). In contrast, in species with high CETP activity, the excess cholesterol from the periphery is transferred from the typical non-apoE-containing HDL to the lower density lipoprotein classes (VLDL, IDL, and LDL) for clearance by the liver. 

Although the amino- and carboxyl-terminal structural domains of apoE appear to be independently folded in the lipid-free state, as discussed in Section 1I,C, there are several examples wherein amino acid substitutions in one domain appear to affect the properties of the other domain. These effects fall into one of two general categories (1) the effect on the distribution of apoE among the various lipoprotein classes and (2) the effect on receptor-binding activity. 

The determination of the three-dimensional crystal structure of the 22-kDa fragment of apoE in 1991 represented a major milestone in the studies of the structure and function of apoE. With this structure, it is now possible to understand and interpret much of what was known previously about the protein. In addition, identification of the structures of the apoE2 and apoE4 variants provides new insight into how apoE interacts with the LDL receptor and how the preference for different lipoprotein classes might be influenced by structure. These structures represent the beginning of the next level of understanding of how... 

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