Cholesterol esters plasma lipoproteins, association with

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. 

Most of the mention of cholesterol in the popular press positions this molecule as a threat to human health. Many foods are proudly labeled cholesterol-free. People are properly warned to pay attention to their plasma cholesterol level, particnlarly that carried in the low-density lipoproteins, LDLs, commonly known, with pretty good reason, as bad cholesterol. LDLs are lipoprotein particles containing a large protein known as B-100 associated with cholesterol, cholesteryl esters, phospholipids, and some triglycerides. 

Most plasma cholesterol is in an esterified form (with a fatty add attached at C-3, see Figure 18.2), which makes the structure sen more hydrophobic than free cholesterol. Cholesteryl esters are rot found in membranes, and are normally present only in low levels in most cells. Because of their hydrophobicity, cholesterol and ils esters must be transported in association with protein as a compo nent of a lipoprotein particle (see p. 225) or be solubilized by phos pholipids and bile salts in the bile (see p. 223). 

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. 

More recently the term hyperlipoproteinemia has become useful. Saturated fatty acids, usually esterified to glycerol as triacylglycerides (i.e., fats), can be related to cardiovascular disease since they increase plasma cholesterol levels. This cholesterol is now known to be primarily associated with a low-density lipoprotein (LDL) fraction. Lipoproteins are complex particles consisting of proteins, triacylglycerol (fat), phospholipids, cholesterol, and cholesterol esters. LDL has density of 1.00-1.06 and contains at least 45% cholesterol. It is the cholesterol found in the LDL fraction that is the harbinger of human arterial plaque manifested as atheroma. An inverse relationship has been established between cholesterol in high-density lipoprotein (HDL) (d = 1.20, 18% cholesterol) and CHD. HDL transports cholesterol from accumulation in arterial walls to the liver for biodegradation. 

Cholesterol esters are considerably more hydrophobic than cholesterol itself. The amounts of cholesterol and cholesterol esters associated in blood lipoprotein complexes called LDL are typically about two-thirds of the total plasma cholesterol (total plasma cholesterol ranges from 130 to 260 mg/100 mL of human plasma, with the most desirable levels between 160 and 200). More than 40% of the weight of the LDL particle is cholesterol esters, and the total of esterified and free cholesterol amounts to well over half the total weight. 

Chronic parenchymal liver disease is associated with relatively predictable changes in plasma lipids and lipoproteins. Some of these changes are related to a reduction in the activity of lethicin cholesterol acyltransferase (LCAT). This plasma enzyme is synthesized and glycosylated in the liver then enters the blood, where it catalyzes the transfer of a fatty acid from the 2-position of lecithin to the Sp-OH group of free cholesterol to produce cholesterol ester and lysolecithin. As expected, in severe parenchymal liver disease, in which LCAT activity is decreased, plasma levels of cholesterol ester are reduced and free cholesterol levels normal or increased. 

The major lipids found in the bloodstream are cholesterol, cholesterol esters, triglycerides, and phospholipids. An excess plasma concentration of one or more of these compounds is known as hyperlipidemia. Because all lipids require the presence of soluble lipoproteins to be transported in the blood, hyperlipidemia ultimately results in an increased concentration of these transport molecules, a condition known as hyperlipoproteinemia. Hyperlipoproteinemia has been strongly associated with atherosclerotic lesions and coronary heart disease (CHD) (1,2). Before discussing lipoproteins, their role in cardiovascular disease, and agents to decrease their concentrations, it is essential to examine the biochemistry of cholesterol, triglycerides, and phospholipids. 

The metabolism of HDL involves several different enzymes and transfer proteins but is not completely understood [7]. The major apolipoprotein of HDL is apoA-I. The liver and intestine are the sources of apoA-I, which interacts with peripheral cells to remove excess cellular cholesterol via the ATP-binding cassette protein A1 (ABCAl). Unesterified cholesterol associated with nascent HDL is a substrate for the plasma enzyme lecithin cholesterol acyltransferase (LCAT), resulting in the formation of cholesteryl ester and enlargement of the HDL particle. Genetic defects in apoA-I, ABCAl and LCAT can cause low levels of HDL, termed hypoalphalipopro-teinemia. HDL cholesteryl ester is transferred to apoB-containing lipoproteins (such as LDL) by the cholesteryl ester transfer protein (CETP) and can be returned to the liver via the LDL receptor. HDL may also deliver some cholesterol directly to the liver via the scavenger receptor class BI (SR-BI). The removal of excess cholesterol from peripheral cells and delivery to the liver for excretion in the bile is a process that has been termed reverse cholesterol transport . 

The fatty acid esters of cholesterol are widely distributed in animal tissues and they have been subjected to in depth biochemical studies because of their importance as constituents of plasma lipoproteins and their association with pathological conditions such as atherosclerosis. Steryl esters are also well established as constituents of various tissues from many plants. However, the biochemistry of the steryl esters in plants has been the subject of rather few studies when compared to the attention received by animal... 

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-... 

An inherited lack of, or deficiency in, cell surface receptors for low density lipoproteins results in a condition, familial hypercholesterolaemia, in which blood cholesterol concentrations are rather high. This condition, if untreated, leads to severe vascular disease and death from ischaemic heart disease. Lipids are involved in several ways. First, one of the characteristics of developing atherosclerotic plaques is an accumulation of lipids, particularly cholesteryl esters, which are derived from plasma lipoproteins secondly, lipids are involved (because of their role as precursors of eicosanoids) in the formation of thrombi which may block arteries and cause ischaemia. Another risk factor for ischaemic heart disease that involves lipid metabolism is obesity, characterized by an excessive accumulation of adipose tissue. In particular, upper body obesity is also associated with Type II diabetes and hyperinsulinaemia. Hyperlipoproteinaemia is secondary to obesity and diabetes mellitus and if these conditions are treated, blood lipid concentrations return to normal. 

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