Plasma lipoprotein cholesterol esters

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. 

In blood, unesterified or free cholesterol experiences countless exchanges among the following blood components [17] (i) between lipoproteins of the same or different types, (ii) between plasma membranes and all types of lipoproteins, and (iii) between red cells and various lipoproteins. These cholesterol exchanges among various lipoprotein species are extremely rapid because they involve transfer of cholesterol molecules mostly situated at the surface of lipoprotein complexes. On the other hand, the exchange rates of cholesterol esters among lipoproteins are much slower. This is because transfer of the cholesterol ester molecule between two lipoprotein complexes must involve first the exit of the ester molecule from the nonpolar core of one... 

An enzyme which catalyses the formation of cholesterol esters by the transfer of fatty acids from lecithin to the cholesterol of plasma lipoproteins (especially high density lipoproteins). A rare inborn error occurs in which there is a deficiency of this enzyme. Patients with this condition have high plasma levels of un-esterified cholesterol. 

When most lipids circulate in the body, they do so in the form of lipoprotein complexes. Simple, unesterified fatty acids are merely bound to serum albumin and other proteins in blood plasma, but phospholipids, triacylglycerols, cholesterol, and cholesterol esters are all transported in the form of lipoproteins. At various sites in the body, lipoproteins interact with specific receptors and enzymes that transfer or modify their lipid cargoes. It is now customary to classify lipoproteins according to their densities (Table 25.1). The densities are... 

Cholesterol (Figure 14-17) is widely distributed in all cells of the body but particularly in nervous tissue. It is a major constituent of the plasma membrane and of plasma lipoproteins. It is often found as cholesteryl ester, where the hydroxyl group on position 3 is esteri-fied with a long-chain fatty acid. It occurs in animals but not in plants. 

Figure 2S-1. Generalized structure of a plasma lipoprotein. The similarities with the structure of the plasma membrane are to be noted. Small amounts of cholesteryl ester and triacylglycerol are to be found in the surface layer and a little free cholesterol in the core.

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. 

Lipoproteins are an important class of serum proteins in which a spherical hydrophobic core of triglycerides or cholesterol esters is surrounded by an amphipathic monolayer of phospholipids, cholesterol and apolipoproteins (fatbinding proteins). Lipoproteins transport lipid in the circulation and vary in size and density, depending on their proteindipid ratio (Figure 7.3). Lipoprotein metabolism is adversely affected by obesity low-density lipoprotein (LDL)-cholesterol and plasma triglyceride are increased, together with decreased high-density lipoprotein (HDL)-cholesterol concentrations. 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

LCAT acts preferentially on lipids transported by HDL (so-called a-LCAT activity), but also on lipids transported by apoB-containing lipoproteins (so-called jS-LCAT activity) [58, 85]. In practice, LCAT activity is measured either as the activity required to esterify radioactive cholesterol that has been exogenously incorporated into native HDL or into artificial HDL-like particles (a-LCAT activity) or which has been equilibrated with endogenous lipoproteins of the plasma sample (cholesterol esterification rate, CER) [21, 58, 85]. Several variations of these assays have been reported, some of which are available as commercial test kits (e.g., Roar Biomedical, New York, USA). In addition, LCAT concentration can be determined by either laboratory-made tests or by a commercial ELISA kits [57]. However, the decrease in LCAT concentration is difficult to judge since it also decreases secondary to HDL deficiency due to causes other than LCAT deficiency. Plasma from patients with LCAT deficiency fails to esterify radioactive cholesterol provided by any substrate. By contrast, plasmas of patients with fish-eye disease show a near-normal cholesterol ester-fication rate but have a selective inability to esterify radioactive cholesterol provided to plasma with native HDL or reconstituted HDL (a-LCAT activity) [58, 85]. 

Cholesterol and cholesteryl esters, like triacylglycerols and phospholipids, are essentially insoluble in water, yet must be moved from the tissue of origin to the tissues in which they will be stored or consumed. They are carried in the blood plasma as plasma lipoproteins,... 

Cholesterol and cholesteryl esters are carried in the blood as plasma lipoproteins. VLDL carries cholesterol, cholesteryl esters, and triacylglycerols from the liver to other tissues, where the triacylglycerols are degraded by lipoprotein lipase, converting VLDL to LDL. 

The liver converts fatty acids to triacyiglycerols, phospholipids, or cholesterol and its esters, for transport as plasma lipoproteins to adipose tissue for storage. Fatty acids can also be oxidized to yield ATP or to form ketone bodies, which are circulated to other tissues. 

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. 

Metabolism of chylomicrons. CM = chylomicron TG = triacylglycerol C = cholesterol CE = cholesteryl esters. Apo B-48, apo C-ll, and apo E are apolipoproteins found as specific components of plasma lipoproteins. 

Composition of the plasma lipoproteins. Note high concentration of cholesterol and cholesteryl esters in LDL. 

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... 

Dietary cholesterol, together with triacylglycerols, is absorbed from the intestinal tract and enters the large lipoprotein chylomicrons (see Fig. 21-1). Absorption of cholesterol is incomplete, usually amounting to less than 40% of that in the diet. Absorption requires bile salts and is influenced by other factors.186 As it is needed cholesterol is taken from the plasma lipoproteins into cells by endocytosis. Much of the newly absorbed cholesterol is taken up by the liver. The liver also secretes cholesterol, in the form of esters with fatty acids, into the bloodstream. 

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. 

Free fatty acids, derived primarily from adipocyte triglycerides, are transported as a physical complex with plasma albumin. Triglycerides and cholesteryl esters are transported in the core of plasma lipoproteins [134], Deliconstantinos observed the physical state of the Na+/K+-ATPase lipid microenvironment as it changed from a liquid-crystalline form to a gel phase [135], The studies concerning the albumin-cholesterol complex, its behavior, and its role in the structure of biomembranes provided important new clues as to the role of this fascinating molecule in normal and pathological states [135]. 

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. 

HI Nishida, H Arai, T Nishida. Cholesterol ester transfer mediated by lipid transfer protein as influenced by changes in the charge characteristics of plasma lipoproteins. J Biol Chem 268 16352-16360, 1993. 

Determination of the rates of esterified cholesterol transfer between plasma lipoproteins has allowed the construction of a model of cholesteryl ester transfer (B7). According to this model, the probability of LTP-I picking up or depositing a molecule of esterified cholesterol in HDL or VLDL or LDL is in the proportion of approximately 30 7 1. Although the probability of in-... 

G6. Glass, C., Pittman, R. C., Weinstein, D. B., and Steinberg, D., Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc. Natl. Acad. Sci. U.S.A. 80, 5435-5439 (1983). 

G24. Goodman, D. S., The in vivo turnover of individual cholesterol esters in human plasma lipoproteins. J. Clin. Invest. 43, 2026-2036 (1964). 

Sniderman, A., Teng, B., Vezina, C., and Marcel, Y. L., Cholesterol ester exchange between human plasma high and low density lipoproteins mediated by a plasma protein factor. Atherosclerosis 31, 327-333 (1978). 

Z8. Zilversmit, D. B., Hughes, L. B., and Balmer, J., Stimulation of cholesterol ester exchange by lipoprotein-free rabbit plasma. Biochim. Biophys. Acta 409, 393-398... 

Cholesterol appears to be taken up from plasma lipoproteins by steroidogenic tissues by two receptor-mediated pathways - the LDL pathway and the HDL pathway. Not all tissues of all species can utilise both of these thus, the LDL pathway appears to occur in all species, including man, whereas the HDL pathway occurs mainly in rodents. LDL lipoproteins interact specifically with cell surface-bound receptors, as shown for, e.g., adrenal [9] and ovary [10], after which internalization occurs by endocytosis and hydrolysis of LDLs, plus their cholesterol ester complement by lysosomal action. 

Lipoproteins are endogenous lipid carrier systems comprising a lipid core and a coat where apolipoproteins can be found. The lipid core material consists of cholesterol and other lipids (cholesterol esters, triacylglycerols and phospholipids) which are transported in plasma and other body fluids in the form of lipoproteins. The ratio of lipid to protein determines the densities of the different lipoproteins ... 

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