Apolipoproteins/apoproteins

Lipoproteins are globular, micelle-like particles consisting of a hydrophobic core of triacylglycerols and cholesterol esters surrounded by an amphipathic coat of protein, phospholipid and cholesterol. The apolipoproteins (apoproteins) on the surface of the lipoproteins help to solubilize the lipids and target the lipoproteins to the correct tissues. There are five different types of lipoprotein, classified according to their functional and physical properties chylomicrons, very low density lipoproteins (VLDLs), intermediate density lipoproteins (IDLs), low density lipoproteins (LDLs), and high density lipoproteins (HDLs). The major function of lipoproteins is to transport triacylglycerols, cholesterol and phospholipids around the body. 

Lipoproteins are macromolecules comprising proteins (= apolipoproteins, apoproteins) and lipids. They transport water-insoluble lipids in the blood, with the exception of the albumin-bound free fatty acids. Only short-chain fatty acids are dissolved in plasma. The lipoproteins are formed in the liver and in the mucosa of the small intestine. (14)... 

The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules (Figure 25-1). These are oriented so that their polar groups face outward to the aqueous medium, as in the cell membrane (Chapter 14). The protein moiety of a lipoprotein is known as an apo-lipoprotein or apoprotein, constituting nearly 70% of some HDL and as litde as 1% of chylomicrons. Some apolipoproteins are integral and cannot be removed, whereas others are free to transfer to other hpoproteins. 

Lipoproteins have hydrophobic core regions containing cholesteryl esters and triglycerides surrounded by unesterified cholesterol, phospholipids, and apoproteins. Certain lipoproteins contain very high-molecular-weight proteins that exist in two forms B-48, formed in the intestine and found in chylomicrons and their remnants and B-lOO, synthesized in liver and found in VLDL, VLDL remnants(IDL),LDL (formed from VLDL), and Lp(a) lipoproteins. HDL consist of at least 15 discrete molecular species. All species contain apolipoprotein A-I (apoA-I). Fifty-three other proteins are known to be distributed variously among the HDL species. 

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). 

Increased levels of apolipoproteins and rate-limiting enzymes of lipogenesis and their mRNAs have been demonstrated in the liver of nephrotic rats (V5), although increased liver cholesterol synthesis has not been confirmed in nephrotic patients (D9). Cholesterol synthesis in the liver probably does not change during antipro-teinuric treatment (D9). The rate of synthesis of LDL apoprotein B is variable and depends on the presence or absence of hypertriglyceridemia (V6). 

W17. Windier, E., Chao, Y., and Havel, R. J., Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apoproteins. J. Biol. Chem. 255, 8303-8307 (1980). 

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. 

Chylomicrons are triglyceride rich and contain apolipoprotein B-48 and the A types. The latter are synthesized in the intestinal tract cells. Additional apoproteins are transferred to the chylomicrons from HDL in circulation the apoE and apoC types. Their site of synthesis is the liver. The chylomicrons are subject to degradation by lipoprotein lipase in the peripheral tissue, especially adipose tissue. Lipoprotein lipase activity is increased by increased blood insulin levels. This enzyme is extracellular, attached to the capillary endothelial cells, and activated by ApoC-II, which is present in the chylomicrons. Lipoprotein lipase causes the hydrolysis of triglycerides, thus decreasing chylomicron size... 

Triacylglycerols and cholesterol are exported from the liver as nascent VLDL complexes, destined primarily to muscle and adipose tissues. The VLDL complex contains apolipoprotein B-lOO and acquires C-I, C-II, C-III and E from circulating HDL complexes. Fatty acids are released from VLDLs in the same way as chylomicrons, through the action of LPL. This action, coupled to a loss of certain apoproteins (the apo-Cs), converts VLDLs to intermediate-density lipoproteins (IDLs), also termed VLDL remnants. The apo-Cs are transferred to HDLs. The predominant remaining proteins are apo-B-100 and apo-E. Further loss of triacylglycerols converts IDLs to LDLs. 

Fig. 2. A model for lipoprotein structure based on the interactions between apolipopro-teins and lipid constituents. The surface monolayer is composed of phospholipids and apolipoproteins. The apoproteins contain helical regions which are amphipathic. The hydrophobic surface of the amphipathic helix interacts with the fatty acyl chains of phospholipids, and the hydrophilic surface is exposed to the aqueous environment of the polar head groups and the plasma. Adapted from Pownall et al.. (1981).

In the intestinal mucosal cells, the triacylglycerols are resynthesized from fatty acids and monoacylglycerols and then packaged into lipoprotein transport particles called chylomicrons, stable particles ranging from approximately 180 to 500 nm in diameter (Figure 22.5). These particles are composed mainly of triacylglycerols, with apoprotein B-48 as the main protein component. Protein constituents of lipoprotein particles are called apolipoproteins. Chylomicrons also function in the transport of fat-soluble vitamins and cholesterol. 

After its absorption into the intestinal mucosal cell, cholesterol, together with triglycerides, phospholipids, and a number of specific apoproteins, is assembled into a large lipoprotein called the chylomicron (see later section on lipoprotein metabolism, exogenous pathway). One apoprotein component known as apolipoprotein (apo) B-48 is vital to the formation of chylomicrons, and in people with a rare deficiency of apo B-48 synthesis, chylomicron formation, and consequently cholesterol and fat absorption, is severely impaired. Chylomicrons enter the lymphatics, which empty into the thoracic duct and eventually enter the systemic venous circulation at the junction of the left subclavian vein and left internal jugular vein. 

Lipoproteins are often called pseudomicellar because their outer shell is in part composed of amphipathic phospholipid molecules. Unlike simple micelles, lipoproteins contain apolipoproteins, or apoproteins, in their outer shell and a hydrophobic core of triacylglycerol and cholesteryl esters. Unesterified, or free, cholesterol, which contains a polar group, can be found as a surface component and in the region between the core and surface (Figure 20-1). Most lipoproteins are spherical. However, newly secreted high-density lipoproteins (HDLs) from the liver or intestine are discoidal and require the action of lecithin-cholesterol acyltransferase (LCAT) in plasma to expand their core of neutral lipid and become spherical. The hydrophobic core of the low-density lipoprotein (LDL) molecule may contain two concentric layers one of triacylglycerol and another of cholesteryl ester. 

Cholesterol and triacylglycerols are transported in body fluids in the form of lipoprotein particles. Each particle consists of a core of hydrophobic lipids surrounded by a shell of more-polar lipids and proteins. The protein components of these macromolecular aggregates, called apoproteins, have two roles they solubilize hydrophobic lipids and contain cell-targeting signals. Apolipoproteins are synthesized and secreted by the liver and the intestine. 

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. 

Lipoproteins are globular, micelle-like particles, with a non-polar nucleus of triglycerides and cholesterol esters, and an amphiphilic 2 nm thick casing of proteins, phospholipids and cholesterol. Being subject to constant metabohc change, their compostition and properties vary. The density of the particles increases with decreasing diameter, since the density of the shell is higher than of the nucleus. The protein portion of the lipoprotein is called the apolipoprotein or apoprotein for short (Fig. 5.145). 

Function Transport dietary TAG and cholesterol from the intestines to the periphery Forward transport of endogenous TAG and cholesterol from liver to periphery Precursor of LDLs Cholesterol transport 1 Reverse transport of cholesterol from periphery to the liver 2 Stores apoprotein C2 and apoprotein E which it supplies to chylomicrons and VLDLs 3 Scavenges and recycles apolipoproteins released from chylomicrons and VLDL following lipoprotein lipase activity in the capillaries... 

Although apoprotein A-IV exhibits the properties of an apolipoprotein [2], and recent data on its sequence [11, 12, 21] have shown that it contains 14.5 tandemly repeated docosapeptides that possess the potential to form amphipathic a-helices [11], it is mainly found unassociated with lipoproteins in human plasma [4,18,19,36]. The Apo A-IV fraction in the lipoprotein-free plasma compartment is still able to bind lipids, as shown by Weinberg and Scanu [37], who were able to reassociate Apo A-IV from the d = 1.21 g/ml infranate to a phospholipid-triglyceride emulsion. After reassociation Apo A-IV could be isolated by flotation in chylomicron-like particles upon ultracentrifugation. 

Weinberg RB, Spector MS (1985) Human apolipoprotein A-IV displacement from the surface of triglyceride-rich particles by HDl -assodated C-apoproteins. J Lipid Res 26 26-37... 

The major LCAT activator is apolipoprotein A-I (ApoA-I) [4], but it has been postulated also that other apolipoproteins may activate LCAT, e. g, the apoproteins C-I, A-IV, and E. We have previously reported that ApoD also activates LCAT, but studies from another laboratory have challenged our proposal. Therefore, we have reinvestigated this problem [5]. 

HDL contain several apolipoproteins. They are ApoA-I, ApoA-II, ApoC, and ApoE. Apoproteins A-I and A-II are the most abundant, the amount of ApoA-I... 

Ghiselh GC, Schaefer EJ, Gascon P, Brewer HB Jr (1981) Type III hyperlipoproteinemia associated with plasma apolipoprotein E deficiency. Science 214 1239-1241 Gualandri V, Franceschini G, Sirtori CR, Gianfranceschi G, Orsini GB, Cerrone A, Menotti A (1985) A-I Milano apoprotein. Identification of the complete kindred and evidence of a dominant genetic transmission. Am J Hum Genet 37 1083-1097... 

A common structural feature of most apolipoproteins is the presence of amphipathic helical structures, which are thought to be responsible for binding apoproteins to lipids of the surface monolayer [60]. Each a-helix contains a hydrophilic and a hydrophobic face the hydrophilic face is exposed to water, whereas the hydrophobic face associates with lipids of the monolayer. Such amphiphilic structure enables apolipoproteins to function as natural surfactants... 

Following the uptake of lipids across the microvillus membrane, thought to occur mainly by passive diffusion, the process of absorption becomes dependent on a series of intracellular events within the mucosal cell. These events include the resynthesis of esterified lipids (triglycerides, phospholipids, cholesteryl esters), the synthesis of chylomicron apolipoproteins (particularly apolipoproteins B, A-I, and A-IV), and the assembly of lipids and apoproteins into chylomicrons. These particles represent the principal lipoprotein vehicles for transporting absorbed lipid out of the intestine and into the general circulation. 

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