Cholesterol esters removal

FIGURE 9-1. Lipoprotein structure. Lipoproteins are a diverse group of particles with varying size and density. They contain variable amounts of core cholesterol esters and triglycerides, and have varying numbers and types of surface apolipoproteins. The apolipoproteins function to direct the processing and removal of individual lipoprotein particles. (Reprinted from LipoScience, Inc. with permission.)... 

Cholesterol ester transfer protein catalyses the transfer of triacylglycerol from VLDL or chylomicrons to LDL and to HDL. However, it is the removal of this triacylglycerol from LDL and HDL, which occurs in the liver, via hepatic lipase, that causes problems small and dense LDL particles, which are more atherogenic than normal... 

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. 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

HDLs have the opposite function to that of LDLs in that they remove cholesterol from the tissues. The HDLs are synthesized in the blood mainly from components derived from the degradation of other lipoproteins. HDLs then acquire their cholesterol by extracting it from cell membranes and converting it into cholesterol esters by the action of LCAT (Fig. 1). The HDLs are then either taken up directly by the liver or transfer their cholesterol esters to VLDLs, of which about half are taken up by the liver by receptor-mediated endocytosis (Fig. 1). The liver is the only organ that can dispose of significant quantities of cholesterol, primarily in the form of bile salts (see Topic K5). 

Both IDL and LDL can be removed from the circulation by the liver, which contains receptors for ApoE (IDL) and ApoB-100 (IDL and LDL). After IDL or LDL interacts with these receptors, they are internalized by the process of receptor-mediated endocytosis. Receptors for ApoB-100 are also present in peripheral tissues, so that clearance of LDL occurs one-half by the liver and one-half by other tissues. In the liver or other cells, LDL is degraded to cholesterol esters and its other component parts. Cholesterol esters are hydrolyzed by an acid lipase and may be used for cellular needs, such as the building of plasma membranes or bile salt synthesis, or they may be stored as such. Esterification of intracellular cholesterol by fatty acids is carried out by acyl-CoA-cholesterol acyltransferase (ACAT). Free cholesterol derived from LDL inhibits the biosynthesis of endogenous cholesterol. B-100 receptors are regulated by endogenous cholesterol levels. The higher the latter, the fewer ApoB-100 receptors are on the cell surface, and the less LDL uptake by cells takes place. 

HDL is synthesised and secreted from the liver and gut and aids the removal of cholesterol from peripheral tissues. It opposes the effects of LDL and protects against coronary heart disease. HDL is the substrate for LCAT, which converts the cholesterol in circulating plasma lipoproteins to cholesterol esters, which are then transferred to other lipoprotein particles. This is termed reverse cholesterol transport. Table... 

Cholesterol is formed in the liver (85%) and intestine (12%) - this constitutes 97% of the body s cholesterol synthesis of 3.2 mmol/day (= 1.25 g/day). Serum cholesterol is esterized to an extent of 70-80% with fatty acids (ca. 53% linolic acid, ca 23% oleic acid, ca 12% palmitic acid). The cholesterol pool (distributed in the liver, plasma and erythrocytes) is 5.16 mmol/day (= 2.0 g/day). Homocysteine stimulates the production of cholesterol in the liver cells as well as its subsequent secretion. Cholesterol may be removed from the pool by being channelled into the bile or, as VLDL and HDL particles, into the plasma. The key enzyme in the synthesis of cholesterol is hydroxy-methyl-glutaryl-CoA reductase (HGM-CoA reductase), which has a half-life of only 3 hours. Cholesterol is produced via the intermediate stages of mevalonate, squalene and lanosterol. Cholesterol esters are formed in the plasma by the linking of a lecithin fatty acid to free cholesterol (by means of LCAT) with the simultaneous release of lysolecithin. (s. figs. 3.8, 3.9) (s. tab. 3.8)... 

D. HDL removes cholesterol from cell membranes. The lecithin cholesterol acyl transferase (LCAT) reaction, which converts the cholesterol to cholesterol esters, occurs on HDL. 

Figure 26-21 Reverse cholesterol transport pathway. HDl High-density lipoproteins LDL, low-density lipoproteins tDL, intermediate-density lipoproteins HTL, hepatic lipoprotein lipase LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein apo E, apoiipoprotein E. Cholesterol is removed from macrophages and other arterial wall cells by an HDL-mediated process. The LCAT esterifies the cholesterol content of HDL to prevent it from reentering the ceils. Cholesterol esters are delivered to the liver by one of three pathways ( ) cholesterol esters are transferred from HDL to LDL by CETP and enter the liver through the specific LDL receptor pathway (2) cholesterol esters are selectively taken from HDL by HDL receptors and HDL particles are returned to circulation for further transport or (3) HDL have accumulated apo E and therefore the particles can enter the liver through remnant receptors, (From Gwynne JT. High density lipoprotein cholesterol levels as a marker of reverse cho/estero/ tronsport./ m j Cardiol I989 64 10G-I7G. Copyright 1989, with permission from Excerpta Medico Inc.)...

Macrophage yS-VLDL receptors may serve a back-up function in cholesterol clearance by facilitating removal of cholesterol-rich ]S-VLDL particles which accompany diet-induced hypercholesterolemia. When dog plasma cholesterol levels exceed 750 mg/dl, )8-VLDL accumulate in plasma and macrophages accumulate cholesterol and cholesterol esters [60]. The association of these events suggests that -VLDL may be taken up by macrophage j8-VLDL receptors for the deposition of plasma cholesterol esters. 

How does cholesterol leave the cell Since most cells do not secrete cholesterol esters (the known exceptions are hepatocytes and intestinal epithelial cells), free cholesterol must take its way to the outer bilayer of the cell membrane, where it may be removed by appropriate acceptors. It is likely that a net loss from the cell membrane involves movement of cholesterol from an area in the membrane with a high cholesterol-phospholipid ratio to an area with a lower ratio in the acceptor. The appropriate acceptors for cholesterol removal include any phospholipid bilayer system that contains little or no free cholesterol [125]. In vivo this is intact or nascent HDL [126,127]. Nascent HDL is a disc of phospholipid surrounded on its hydro-phobic perimeter by detergent-like apoproteins, such as the arginine-rich apoprotein and the HDL apoproteins, apo AI and apo All [128]. It is secreted from the liver and probably from the intestine (Chapter 5) into the plasma. Cholesterol enters nascent or intact HDL, and the lecithin-cholesterol acyltransferase (LCAT) reaction converts it to cholesterol ester [129,130] (Chapter 4). Since the ester is insoluble in the phospholipid bilayer it oils out into the centre of the particle. In this way. nascent discs are converted to spheres, and space for a new substrate, cholesterol, is created at the surface of the particle. Lipoproteins in lymph may also produce. similar effects on the cell surfaces exposed to this fluid. 

Triacylglycerols are dominant and constitute about 98% of milk fat, together with small amounts of di- and monoacylglycerols and free fatty acids. Small quantities of phospholipids, cholesterol, and cholesterol esters are also present as well as the fat-soluble vitamins A, D, and E. Lipid molecules in milk associate to form large spherical globules, which are surrounded by a phospholipid layer, the globule membrane, from the proteins in the milk. This membrane stabilizes the hydrophobic lipid in the aqueous phase of the milk. The emulsion must be broken and the protein film removed before the fat can be separated and determined volumetrically. 

Approximately half of the VLDL remnants are not taken up by the liver but, instead, have additional core triacylglycerols removed to form IDL, a specialized class of VLDL remnants. With the removal of additional triacylglycerols from IDL through the action of hepatic triglyceride lipase within hepatic sinusoids, LDL is generated from IDL. As seen in Table 34.4, the LDL particles are rich in cholesterol and cholesterol esters. Approximately 60% of the LDL is transported back to the hver, where its apoB-100 binds to specific apoB-100 receptors in the hver cell plasma membranes, allowing particles to be endocytosed into the hepatocyte. The remaining 40% of LDL particles are carried to extrahepatic tissues such as adrenocortical... 

HDL Triglycerides 2-7%, free cholesterol 3-5%, oholesterol esters 15-20%, phospholipids 26-32%, apoproteins 45-55% apoA-l, apoA-ll, apoE, apoC-l, apoC-ll, apoC-lll Removal of cholesterol from extrahepatic tissues via transfer of cholesterol esters to IDL and LDL... 

Synthesized in the liver and intestine, HDL initially exists as a dense, phospholipid disk composed primarily of apoA-l. The primary function of HDL is to act as a scavenger to remove cholesterol from extrahepatic cells and to facilitate its transport back to the liver. Nascent HDL accepts free, unesterified cholesterol. A plasma enzyme, lecithin-cholesterol acyltransferase, then esterities the cholesterol. This process allows the resulting cholesterol esters to move from the surface to the core and results in the production of spherical HDL3 particles. As cholesterol content is added, HDL3 is converted ... 

Freeman (1964) has analyzed mixtures of cholesterol esters (e.g., cholesteryl oleate) and triglycerides (e.g., triolein) by using the difference in the positions of the ester carbonyl bands. To analyze serum lipids he first removed phospholipids (1735-cm" ester groups) by adsorbing them on silicic acid. Measurements were then made on carbon tetrachloride solutions of the unadsorbed lipids at 1745 and 1730 cm" the approximate band positions of triglycerides and cholesterol esters, respectively. Minor lipid constituents produced only negligibly small errors and the over-all accuracy was about 5%. Freeman said that with minor modifications in procedure as little as 0.4 ml of serum could be analyzed and with microcells as little as 0.05 ml. 

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