Cholesteryl ester coated

Reports on the applications of h.p.l.c. to specific problems include an efficient separation of the reduction products of progesterone, of the conjugates of natural bile acids, and of 2-hydroxy- and 2-methoxy-oestrogens ( catechol oestrogens). Fluorescence detection is reported to be some 500 times more sensitive than u.v. absorption for h.p.l.c. of oestriol. The h.p.l.c. behaviour of compounds in the vitamin D series appears to be correlated with the degree of molecular planarity. " A first report on the use of cholesteric liquid crystals as stationary phases for h.p.l.c. shows promise. Various cholesteryl esters coated on or bonded to Corasil II showed increased capacity factors (k ) when steroids were chromatographed, and permitted some useful separations. 

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

The triacylglycerols and cholesteryl esters form the hydrophobic core of the chylomicrons, which are coated with surface phospholipids, free cholesterol, and apolipoprotein B-48. 

Lipoproteins have a spherical core of neutral lipids, such as cholesteryl esters and triacylglycerols, which is coated with unesterifed cholesterol, phospholipids, and apoUpoproteins. 

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. 

This general model is now universally accepted, though there are minor reservations [e.g., both cholesteryl ester (S39) and triglyceride (H4) have limited solubility in phospholipid, and hence a fraction of these hydrophobic core lipids is probably found in the outer coat of lipoprotein lipid]. 

LDL binds specifically to lipoprotein receptors on the cell surface. The resulting complexes become clustered in regions of the plasma membrane called coated pits. Endocytosis follows (see Fig. 13-3). The clathrin coat dissociates from the endocytic vesicles, which may recycle the receptors to the plasma membrane or fuse with lysosomes. The lysosomal proteases and lipases then catalyze the hydrolysis of the LDL-receptor complexes the protein is degraded completely to amino acids, and cholesteryl esters are hydrolyzed to free cholesterol and fatty acid. New LDL receptors are synthesized on the endoplasmic reticulum (ER) membrane and are subsequently reintroduced into the plasma membrane. The cholesterol is incorporated in small amounts into the endoplasmic reticulum membrane or may be stored after esterification as cholesteryl ester in the cytosol this occurs if the supply of cholesterol exceeds its utilization in membranes. Normally, only very small amounts of cholesteryl ester reside inside cells, and the majority of the free cholesterol is in the plasma membrane. 

The topic of lipoproteins is the most complicated issue presented in this chapter. Lipoproteins are complexes of specific proteins and lipids. Each lipoprotein contains different proportions of various lipids. The constant component of any one type of lipoprotein is the protein hence, the structure or function is described by first naming the protein. Lipoproteins are synthesized primarily in the intestines and liver and are secreted into the plasma, where their function is to transport various Lipids. Lipoproteins are water soluble because of their outside coat of proteins and the hydrophilic phosphate groups of their phospholipids. This water solubility enables lipoproteins to transport the triglycerides and cholesteryl esters that reside within their cores. An understanding of lipoproteins is useful to individuals interested in energy metabolism and essential to those concerned with cardiovascular disease. 

LDL have bound to LDL receptors. The coated region surrounding the bound receptor, referred to as a coated pit, pinches off and becomes a coated vesicle. Subsequently, uncoated vesicles are formed as clathrin depolymerizes. Before uncoated vesicles fuse with lysosomes, LDL are uncoupled from LDL receptors as the pH changes from 7 to 5. (This change is created by ATP-driven proton pumps in the vesicle membrane.) LDL receptors are recycled to the plasma membrane, and LDL-containing vesicles fuse with lysosomes. Subsequently, LDL proteins are degraded to amino acids, and cholesteryl esters are hydrolyzed to cholesterol and fatty acids. 

The receptor SR-BI differs In two Important respects from the LDL receptor. First, SR-BI clusters on microvilli and in cell-surface lipid rafts (Chapter 5), not In coated pits as does the LDL receptor. Second, SR-BI mediates the transfer of lipids across the membrane, not endoc3rt osIs of entire LDL particles as mediated by the LDL receptor. A multifunctional receptor, SR-BI can mediate the selective uptake from lipoproteins of diverse lipids (e.g., cholesteryl esters, vitamin E) it also functions in the reverse direction to facilitate the export of unesterified cholesterol from cells to bound lipoproteins. SR-BI has a structure similar to that of the fatty acid transporter CD36, and they both belong to the superfamily of scavenger receptors as discussed later, some of these receptors apparently play a role In the onset of atherosclerosis. 

LDL consist of a lipid core of cholesteryl esters and triglycerides surrounded by a coat of cholesterol and phospholipids. The coat contains several molecules of vitamin E and apolipoprotein. Under oxidant stress, both lipids and protein are oxidized. The breakdown of the PUFA yields aldehydes and ketones of small molecular weight, which go on to react further. These structural changes ensure that oxidized LDL ceases to be a substrate for the LDL receptor instead it becomes a substrate for the scavenger receptor. 

A specific type of interaction between lipids and proteins is found in lipoproteins which transport triglycerides and cholesteryl esters in the plasma of mammalians. The largest lipoproteins, chylomicrons with a diameter between 800 A and 5000 A, and very-low-density lipoproteins (VLDL), with a diameter of 300-800 A, resemble emulsion droplets with a core of non-polar lipid and a surface coat of phospholipids and proteins (cf. Brown et ai, 1981). A physical characterization of chylomicrons has been reported (Parks et al.y 1981). Most of the plasma cholesterol occurs in low-density lipoprotein (LDL) which is a particle with a diameter of 200 A. The core consists of almost pure cholesteryl esters and a surface coat of a phospholipid monolayer and four tetrahedrally arranged apoproteins (Gulik-Krzywicki et aly 1979). The smallest particle, high-density lipoprotein (HDL), is a kind of molecular lipid-protein complex. 

Figure 37.4 Lipoproteins. Lipoproteins are macromolecular complexes used by the body to transport lipids in the blood. They are characterised by an outer coat of phospholipids and proteins, which encloses an inner core of hydrophobic TAG and cholesteryl ester. Lipoproteins tire classified according to the way they behave on centrifugation. This in turn corresponds to their relative densities, which depends on the proportion of (high density) protein to (low density) lipid in their structure. For example, high density lipoproteins (HDLs) consist of 50% protein and have the highest density, while chylomicrons (1% protein) tmd very low density lipoproteins (VLDLs) have the lowest density.

Triacylglycerols and cholesteryl ester are enveloped by a coat of phospholipids, apoAl and apoB48 to form nascent chylomicrons. 

Figure 4.46 Lipid bilayer model of LDL structure. From Lewis [313]. Lewis describes the model in this way A protein network is envisaged, with icosahedral symmetry it is suggested that there are 60 such units, existing as trimers. Instead of the conventional view of a protein>coated molecule with a lipid core, it was proposed that the lipids are org-aized into a spherical bilayer. The two lipid layers are mirror images, the non-polar regions of their main constituents, phospholipid and cholesteryl ester, oriented towards each other. At the outer surface of the outer layer and the inner surface of the inner layer are situated the polar groups of the phospholipids and the cholesterol side chains these regions of the major constituents are thus adjacent to the protein units on the surface and to a presumptive protein component at the centre of the particle. ...

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