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Fig. 5.6 The HDL pathway. Lipid-poor apoAI or pre-pi HDL acquires phospholipids (PL) and free cholesterol (FC) by interaction with cell membranes, forming discoidal HDL in the circulation. Through the action of lecithin-cholesterol acyltransferase (LCAT), and the acquisition of further lipids arising during the action of lipoprotein lipase (LPL) on triacylglycerol-rich particles (TRL) [phospholipid transfer protein, PLTP, is involved in this transfer], these particles swell and become spherical 'mature HDL'; smaller spherical particles are known as HDL3; more lipid-rich particles as HDL2. (Fatty acids, FA, are also produced by the action of LPL, and the smaller particles that remain are known as remnants (rem).) These mature HDL particles can deliver their lipid content to the liver, possibly via the receptor SR-BI (see Section 5.2.4.4), to recycle as lipid-poor apoAI. An alternative route for delivery of lipid to the liver is through transfer of TRL remnants via the cholesteryl ester transfer protein (see Fig. 5.11). Based on Fielding, P.E. & Fielding, C.J. (1996) in Biochemistry of Lipids, Lipoproteins and Membranes (eds. D.E. Vance & J. Vance), pp. 495-516. Elsevier, Amsterdam.

5.2.4 Specific lipoprotein receptors mediate the cellular removal of lipoproteins and of lipids from the circulation

One function of the apolipoproteins has already been described as targeting of lipoproteins to specific destinations. This is achieved by the interaction of the apolipoproteins with specific cell-surface receptors. The triacylglycerol-rich lipoprotein particles, chylomicrons and VLDL, are largely confined to the vascular compartment by their size until they have undergone extensive lipolysis, allowing them to pass through the fenestrations in the endothelial lining of the capillaries. Some of the receptors involved are therefore expressed on endothelial cells, but most are expressed on parenchymal cells, and part of their selectivity may depend upon the exclusion, by virtue of size, of the larger particles. Before describing the major receptors involved in lipoprotein metabolism in further detail, it is useful to make some general points about membrane-bound receptors.

5.2.4.1 Membrane receptors

Membrane receptors are proteins designed to recognize specific molecules and bind them in preparation for the initiation of a biological process that takes place in the membrane. The process may be the transport of a molecule (e.g. glucose, LDL) across the membrane or the triggering of a chemical message by a hormone or a growth factor. The recognition step demands that the receptor has specificity, like an enzyme for its substrate. Binding is followed frequently, but not always, by inter-nalization in which the membrane in the vicinity of the receptor forms a vesicle that encapsulates the receptor-ligand complex and enters the cell. Once inside, the receptor complex can be degraded by lysosomal enzymes and the receptor proteins may be recycled to be reinserted into the plasma membrane again. The number of membrane receptors is usually responsive to the availability of the specific ligand. This requires a mechanism for the control of the biosynthesis of the receptor. Receptors are usually glycoproteins, as described for the LDL-receptor below. The functional properties of receptors in membranes appear to be intimately related to the microenvironment provided by membrane lipids. Membrane proteins are on average associated with 30-40 molecules of phospholi-pid per molecule of peptide. These annular phospholipids are required for functional activity or for the stabilization of protein conformation. The structural and compositional changes of the lipid bilayer, which provides a fluid matrix for proteins, can induce alterations in functional properties of proteins in the intact membrane, for example by allowing changes in protein conformation or the diffusion or position of proteins in the membrane.

This may be an important means by which diet -affecting the nature of the membrane phospholipid fatty acids - can affect hormone action, for instance.

5.2.4.2 The LDL-receptor

The best-characterized lipoprotein receptor is the LDL-receptor, also known as the B/E receptor because it recognizes (i.e. binds to) homologous regions on apolipoprotein E and on apolipoprotein B100 (but not apoB48). Mutations in this receptor causing loss of function result in marked elevation in the plasma LDL-cholesterol concentration, the condition known as familial hypercholesterolaemia (Section 5.4.2). It is the receptor responsible for the removal of LDL particles from the circulation. The structure of this receptor is shown in Fig. 5.7.

The receptor is synthesized on the rough endo-plasmic reticulum as a precursor of molecular mass 120 kDa. About 30 min after its synthesis, the protein is modified to a mature receptor with an apparent mass of 160 kDa. The increase in molecular mass coincides with extensive modifications of the carbohydrate chains. The precursor molecule contains up to 18 N-acetylglucosamine molecules attached in O-linkage to serine and threonine residues (Fig. 5.7) as well as two high mannose-con-taining N-linked chains. The latter are modified extensively and the O-linked chains are elongated by addition of one galactose and two sialic acid residues to each N-acetylglucosamine during post-translational processing in the Golgi network.

The receptor is exported to specialized regions of the cell membrane known as coated pits, where the cytoplasmic leaflet is coated with the protein cla-thrin. After binding of an LDL particle through interaction of its apolipoprotein B100 molecule with the ligand-binding domain of the LDL-receptor, the receptor-LDL complex is internalized by endocy-tosis of the coated pit (Fig. 5.8). The coated vesicle so formed loses its clathrin coating, and its interior becomes acidified (an endosome). The LDL particle and receptor dissociate in the low pH environment of the endosome, and the receptor is recycled back to the cell surface. The remainder of the particle is transferred to lysosomes, where the cholesteryl esters are hydrolysed by lysosomal acid hydrolases,

Fig. 5.7 The structure of the LDL-receptor and related receptors. (The apoE receptor 2 is not shown but it is similar to the LDL and VLDL-receptors.) Each of the receptors in this family is built up from repeats of simpler units, some named according to their homology with the epidermal growth factor (EGF) receptor. The ligand binding domains are responsible for binding to the apolipoproteins of the target lipoprotein particles. The internalization signal domain is responsible for internalization of the receptor after the ligand is bound. Based upon Fig. 4 in Schneider, W.J. (1996) in Biochemistry of Lipids, Lipoproteins and Membranes (eds. D.E. Vance & J. Vance), pp. 517-541. Elsevier, Amsterdam.

Fig. 5.7 The structure of the LDL-receptor and related receptors. (The apoE receptor 2 is not shown but it is similar to the LDL and VLDL-receptors.) Each of the receptors in this family is built up from repeats of simpler units, some named according to their homology with the epidermal growth factor (EGF) receptor. The ligand binding domains are responsible for binding to the apolipoproteins of the target lipoprotein particles. The internalization signal domain is responsible for internalization of the receptor after the ligand is bound. Based upon Fig. 4 in Schneider, W.J. (1996) in Biochemistry of Lipids, Lipoproteins and Membranes (eds. D.E. Vance & J. Vance), pp. 517-541. Elsevier, Amsterdam.

and the cholesterol adds to the cellular cholesterol pool. Cholesteryl esters may also be resynthesized by the action of acyl-CoA: cholesterol acyltransfer-ase. The size of this cellular cholesterol pool in turn regulates expression of the LDL-receptor so that cellular cholesterol content is strongly regulated, as described in Section 5.3.1

LDL-receptors are expressed by most cell types. There is some debate, however, about their biological function. They represent a means by which cells can acquire cholesterol exported from the liver. Most cells expressing LDL-receptors, however, also have the enzymic capability of synthesizing cholesterol de novo, from acetyl-CoA. The alternative view is that LDL-receptors are there to remove cholesterol from the plasma. The fact that they are highly expressed in steroidogenic tissues such as the adrenal cortex argues for the former. However, in whole-body terms, the main site of LDL-receptor-mediated LDL removal is the liver.

Cholesterol delivered to the liver can be removed from the body either by excretion directly in the bile, or after conversion to bile salts. Increasing LDL-receptor activity with the 'statin7 drugs (see Section 5.3.1) can lead to marked reduction in plasma cholesterol concentration.

5.2.4.3 The LDL-receptor-related protein and other members of the LDL-receptor family

Because of its ability also to bind apoE, the LDL-receptor may play a role in removal of chylomicron remnants from the circulation. But it cannot be the major receptor involved in this process, because humans or animals lacking functional LDL-recep-tors (as in familial hypercholesterolaemia) do not show accumulation of chylomicron remnants. Recently a related receptor has been identified, known as the LDL-receptor-related protein or LRP. This is the best candidate at present for the

Fig. 5.8 Cell biology of the LDL-receptor. Acyl-CoA cholesterol acyltransferase (ACAT) synthesizes cholesteryl esters that may be stored in the cell. The synthesis of the LDL-receptor is closely regulated at the level of gene expression by the cellular cholesterol content (see Fig. 5.13). Redrawn from Frayn, K.N. (1996) Metabolic Regulation: a Human Perspective (Portland Press), and Krieger, M. (1999) Annual Review of Biochemistry, 68, 523-558.

Fig. 5.8 Cell biology of the LDL-receptor. Acyl-CoA cholesterol acyltransferase (ACAT) synthesizes cholesteryl esters that may be stored in the cell. The synthesis of the LDL-receptor is closely regulated at the level of gene expression by the cellular cholesterol content (see Fig. 5.13). Redrawn from Frayn, K.N. (1996) Metabolic Regulation: a Human Perspective (Portland Press), and Krieger, M. (1999) Annual Review of Biochemistry, 68, 523-558.

chylomicron remnant receptor. The LDL-receptor and LRP, together with the other receptors (described below), form a family of receptors with structural homologies (Fig. 5.7).

LRP binds to apoE, in which chylomicron remnants are relatively enriched. It is expressed in most tissues, with the liver, brain and placenta as major sites of expression on a whole-body basis. Its expression is not regulated by cellular cholesterol content as is that of the LDL-receptor. However, in adipocytes, where it is also expressed, its concentration on the cell surface is rapidly increased by insulin. This increase in receptor appearance on the cell membrane is too rapid to be accounted for by an effect of insulin on protein synthesis, leading to the suggestion that the LRP, like the glucose transporter GLUT4, is present within the cells and translocates to the cell membrane when stimulated by insulin. This would represent a mechanism for directing some chylomicron remnants to adipose tissue in the period following a meal, although the major site of chylomicron remnant uptake is still considered to be the liver.

Both hepatocytes and adipocytes also produce apolipoprotein E, which may be expressed on the cell surface. In the liver it has been suggested that chylomicron remnants, once they become small enough via the activity of lipoprotein lipase in the capillary beds of other tissues, may enter the sub-

endothelial space (the space of Disse). Here they bind to hepatic lipase, which is also expressed on the hepatocyte membrane. Further triacylglycerol hydrolysis by hepatic lipase alters the particle composition so that cell membrane-attached apoE binds to the particle. As the remnant particle becomes further enriched with apoE by this means, it binds to adjacent LRP and is then internalized by a process very similar to that described for the LDL-receptor (Fig. 5.8). Lipoprotein lipase also binds to the LRP. Since lipoprotein lipase is not synthesized in the adult liver, it is presumed that remnant particles carry this enzyme from peripheral tissues to the liver, where it assists in binding of the particles to LRP.

Unlike the case for LDL-receptor, no human LRP deficiency state has yet been found. Attempts to create mice lacking the LRP have not been successful - the phenotype is lethal at an early embryonic stage. It may therefore be an essential protein for life.

A related receptor protein was discovered in 1992 by searching for genes with homology to the LDL-receptor gene. This receptor binds to, and internalizes, VLDL particles particularly avidly. It is expressed mainly in tissues outside the liver that might be expected to have a requirement for fatty acids: heart, skeletal muscle and adipose tissue. Within those tissues the so-called VLDL-receptor is expressed mainly by the endothelial cells, which suits its supposed role as a receptor for large, tria-cylglycerol-rich particles that cannot cross the endothelial barrier. The precise physiological role of the VLDL-receptor is unknown, however. Its structure is shown in Fig. 5.7.

A further member of the family in mammals is known as megalin or lipoprotein receptor-related protein-2 (LRP-2; Fig. 5.7). It is expressed in absorptive epithelial cells of the proximal tubules of the kidney. It has been suggested that its function is the re-uptake of fat-soluble vitamins that would otherwise be lost by urinary excretion. In 1996 yet another member of the family was described, the apoE receptor 2. This is, again, closely homologous to the LDL and VLDL-receptors. It is highly expressed in the brain and may play a role in lipid transport into the central nervous system.

This family of receptors is related also to the vitellogenin receptor responsible for delivery of lipid to the developing avian egg yolk, and there are closely related proteins in the fly Drosophila melanogaster and the nematode Caenorhabditis ele-gans (Fig. 5.7).

5.2.4.4 Scavenger receptors

Unrelated structurally to the LDL-receptor family are several receptors with the generic name of 'scavenger receptors'. These were first identified as receptors in macrophages that mediate the uptake of LDL particles that have been chemically modified so that their affinity for the LDL-receptor is reduced. One such modification is oxidation, the significance of which will be discussed in Section 5.4.1. There are at least three families of scavenger receptors, classes A, B and C. They are characterized by a broad substrate specificity, and they may well have roles in macrophage function in host defence, removal of foreign substances, etc., beyond their role in lipid metabolism. There are two related receptors in class A, the type I and type II scavenger receptors. They are expressed on the macrophage cell surface in clathrin-coated pits, similar to the LDL-receptor (Fig. 5.8). They bind and internalize modified LDL particles, which are then degraded by similar processes to those shown in Fig. 5.8.

However, a crucial difference from the LDL-receptor system is that the cellular cholesterol content does not regulate expression of the scavenger receptors. Thus, their activity can lead to unregulated accumulation of cholesterol in macrophages, an event that may initiate the series of changes that lead to atherosclerosis (Section 5.4.1).

Class B scavenger receptors include the receptor known as Scavenger Receptor Class B type 1 or SR-BI, and a protein that had been previously studied as a widely expressed cell-surface antigen given the name CD36. SR-BI was found to bind HDL particles with high affinity, and is now recognized as a long-sought HDL receptor. Its function in this role is covered in more detail in the following section. CD36 appears to have multiple roles. Amongst other physiological roles, it has been suggested as a long-chain fatty acid transporter and also given the name fatty acid translocase (FAT).

5.2.5 The lipoprotein particles transport lipids between tissues but they interact and are extensively remodelled in the plasma compartment

It is convenient to describe lipoprotein metabolism as consisting of three pathways, but it will become clear that these are interrelated and interact with one another.

The pathway for transport of dietary fat is known as the exogenous pathway (Fig. 5.9). As the tri-acylglycerol-rich chylomicron particles, secreted from enterocytes, enter the plasma, they interact with other particles (presumably by simple physical contact) and acquire other apolipoproteins, especially CII, CIII and apoE. ApoCII is essential for their further metabolism. The chylomicron particles come into contact with the enzyme lipoprotein lipase, which is expressed in a number of extra-hepatic tissues that can use fatty acids, including adipose tissue, skeletal and cardiac muscle and mammary gland. Lipoprotein lipase was described in Section 3.5.2. It is anchored to the luminal aspect of the endothelial cells lining the capillaries in these tissues by binding to heparan sulphate proteogly-cans. As chylomicrons pass through the capillaries

Fig. 5.9 Overview of the exogenous and endogenous pathways of lipoprotein metabolism. Lipolysis of particles by lipoprotein lipase (LPL) in capillaries of extra-hepatic tissues is simplified: VLDL particles, in particular, may go through several cycles of lipolysis, and there is an intermediate class of particle known as Intermediate Density Lipoprotein (IDL) formed before final conversion to LDL particles. VLDL particles themselves may also be removed by VLDL receptors expressed in peripheral tissues. Interactions with HDL are shown in part in Fig. 5.11, but HDL is also an important donor of apolipoproteins (e.g. apoCII to nascent chylomicrons). Ideas for this figure came from Herz, J. (1998) in Lipoproteins in Health and Disease (eds. D.J. Betteridge et al.), pp. 333-359. Arnold, London.

Fig. 5.9 Overview of the exogenous and endogenous pathways of lipoprotein metabolism. Lipolysis of particles by lipoprotein lipase (LPL) in capillaries of extra-hepatic tissues is simplified: VLDL particles, in particular, may go through several cycles of lipolysis, and there is an intermediate class of particle known as Intermediate Density Lipoprotein (IDL) formed before final conversion to LDL particles. VLDL particles themselves may also be removed by VLDL receptors expressed in peripheral tissues. Interactions with HDL are shown in part in Fig. 5.11, but HDL is also an important donor of apolipoproteins (e.g. apoCII to nascent chylomicrons). Ideas for this figure came from Herz, J. (1998) in Lipoproteins in Health and Disease (eds. D.J. Betteridge et al.), pp. 333-359. Arnold, London.

they bind to lipoprotein lipase and to the proteoglycan chains. LPL, with apoCII as an essential activator (cofactor), hydrolyses the core triacylgly-cerol in the particle. The rate of lipolysis is rapid, and it has been estimated that somewhere between 10 and 40 lipoprotein lipase molecules must act simultaneously on a chylomicron. The non-ester-ified fatty acids that are generated can diffuse into the adjacent tissues, either by simple diffusion across the cell membranes or by facilitated diffusion, using one of the recently described fatty acid transport proteins (see Section 5.1.3 for a description of this in the enterocyte). The triacylglycerol-depleted chylomicron particle shrinks, and as a consequence some of the amphipathic surface monolayer becomes redundant. Surface components dissociate and are acquired by other lipo-proteins, particularly HDL. A phospholipid-transfer protein in the plasma seems to mediate this transfer. The particle dissociates from lipoprotein lipase (the process of lipolysis having taken perhaps a matter of minutes). It is known as a chylo-micron remnant. It may undergo a further round of lipolysis in another tissue bed, but after loss of about 80% of its original content of triacylglycerol it will be removed rapidly from plasma. Shrinkage of the particle allows it to cross the endothelial barrier and interact with cell-surface receptors. In addition, conformational changes to the apolipoproteins caused by the shrinkage of the particle expose different regions, which bind to specific cell-surface receptors, probably mainly LRP (see Section 5.2.4 above). The half-life of chylomicron-triacylglycerol in the circulation is about 5 min. The half-life of a chylomicron particle has been estimated at 13-14 min.

The exogenous pathway is regulated mainly by the rate of entry of dietary fat, but the tissue disposition of the dietary fatty acids is regulated by tissue-specific regulation of lipoprotein lipase activity. Adipose tissue lipoprotein lipase activity is up-regulated by insulin and therefore plays an important role in removal of dietary fatty acids in the period following a mixed meal (i.e. a meal that contains both fat and carbohydrate, since the latter will stimulate insulin secretion). The mechanism for activation of adipose tissue lipoprotein lipase by insulin is complex. Whilst insulin increases transcription of the lipoprotein lipase gene in adipose tissue, the major point of regulation in the short term (the hours following a meal) appears to be a diversion within the adipocyte of lipoprotein lipase between a degradative pathway, and secretion in an active form for export to the endothelium. Since the enzymes of triacylglycerol synthesis in adipo-cytes are also activated in the fed state, the net effect is that dietary fatty acids tend to be readily deposited as adipocyte triacylglycerol. In contrast, lipoprotein lipase in skeletal, and particularly cardiac, muscle is down-regulated by insulin, and increases in activity during fasting, and in skeletal muscle with exercise training. In these conditions, therefore, fatty acids tend to be directed to the tissues that need them for oxidation (Fig. 5.10).

Fig. 5.10 Tissue-specific regulation of lipoprotein lipase (LPL) in relation to nutritional state directs the flow of triacylglycerol-fatty acids to different tissues according to needs.

The secretion of VLDL from the liver, and its further metabolism, is described as the endogenous pathway (Fig. 5.9). It is very similar initially to the exogenous pathway. VLDL particles also interact with lipoprotein lipase in capillaries and their core triacylglycerol is hydrolysed. The half-life of VLDL particles in the circulation is typically 12 h, but their fates are heterogeneous. As the particles lose their triacylglycerol through successive interactions with lipoprotein lipase, they also lose their surface apo-lipoproteins as described above, until they become LDL particles. However, along the way some of the particles are removed intact by endothelial VLDL-receptors. LDL particles have an even longer halflife in the circulation, typically 2-2.5 days, and they are removed by LDL-receptors on cell surfaces (Section 5.2.4 above) in the sub-endothelial space. The major site for removal of LDL particles is normally the liver although the LDL-receptor is a mechanism for delivering cholesterol to most cells. The expression of LDL-receptors is closely regulated to maintain cellular cholesterol homeostasis (Section 5.3.1). Thus, the endogenous pathway is a means of delivering fatty acids to tissues via lipo-protein lipase and perhaps the VLDL-receptor, and cholesterol via the LDL-receptor.

The third pathway is that of HDL metabolism (Fig. 5.11). As described above, HDL particles may not be secreted as such: rather, the basic components of apoAI and phospholipid are secreted and the particles cycle through various stages in the plasma. If the LDL pathway of cholesterol delivery to tissues is regarded as 'forward cholesterol transport7, the HDL pathway represents 'reverse cholesterol transport7 or the movement of cholesterol out of tissues and its transport to the liver for ultimate excretion in the bile. (The liver is the only mammalian organ that can excrete cholesterol from the body.)

As described earlier (Section 5.2.3 and Fig. 5.6), immature lipid-poor HDL particles (pre-^1 HDL) interact with cell membranes to acquire unester-ified cholesterol. There has been much debate about whether this involves a specific receptor. Recent advances in the molecular biology of cellular cholesterol efflux have come about through the identification of the gene defect in Tangier disease, a rare inherited disease in which cholesterol accumulates in tissues.

The gene responsible for Tangier disease encodes a protein that is a member of a family of cell-membrane-associated transporter proteins that have the property of binding ATP on their cytoplasmic side (through the so-called ATP-binding cassette, ABC: this particular protein has now become known as ABC1). Hydrolysis of ATP can

Fig. 5.11 The pathway of reverse cholesterol transport. For more details of HDL metabolism see Fig. 5.5. Lipid-poor apoAI acquires free cholesterol (FC) and phospholipid from peripheral tissues via the ATP-binding cassette protein-1 (ABC1). The lipid content of the HDL particles is increased by transfer of additional cholesterol from the lipolysis of triacylglycerol-rich lipoprotein (TRL) particles. Esterification of this cholesterol by lecithin-cholesterol acyltransferase (LCAT) produces mature, lipid-rich HDL2 particles. These can return their cholesterol to the liver in two ways. They may deliver it directly via a hepatic receptor (SR-BI) or they may exchange it for triacylglycerol from the TRL via the action of cholesteryl ester transfer protein (CETP). The TRL particles then carry this cholesterol to the liver for receptor-mediated uptake. (CE denotes cholesteryl esters.)

Fig. 5.11 The pathway of reverse cholesterol transport. For more details of HDL metabolism see Fig. 5.5. Lipid-poor apoAI acquires free cholesterol (FC) and phospholipid from peripheral tissues via the ATP-binding cassette protein-1 (ABC1). The lipid content of the HDL particles is increased by transfer of additional cholesterol from the lipolysis of triacylglycerol-rich lipoprotein (TRL) particles. Esterification of this cholesterol by lecithin-cholesterol acyltransferase (LCAT) produces mature, lipid-rich HDL2 particles. These can return their cholesterol to the liver in two ways. They may deliver it directly via a hepatic receptor (SR-BI) or they may exchange it for triacylglycerol from the TRL via the action of cholesteryl ester transfer protein (CETP). The TRL particles then carry this cholesterol to the liver for receptor-mediated uptake. (CE denotes cholesteryl esters.)

then power the transfer of substances across membranes. In the case of cholesterol efflux, ABC1 seems to mediate the transfer of cholesterol from 'cholesterol rafts7 in the cell membrane to the lipid-poor HDL particles (where it binds to apoAI). The unesterified cholesterol acquired by the particles becomes esterified with a long-chain fatty acid through the action of the enzyme lecithin-cholesterol acyltransferase (LCAT), which is associated with HDL particles. This enzyme catalyses the transfer of a fatty acid from phosphatidylcholine to cholesterol to form a cholesteryl ester (Fig. 5.12). The phospholipid substrate for the reaction is pre sent in the HDL particle. The hydrophobic choles-teryl ester moves to the core of the particle, which swells and becomes spherical as more cholesterol is acquired and esterified. The other product, lyso-phosphatidylcholine, is transferred to plasma albumin from which it is rapidly removed from blood and reacylated. This is probably the origin of the bulk of HDL-cholesterol in plasma, although some is also acquired from the surface components of chylomicrons and VLDL particles when their triacylglycerol is hydrolysed by lipoprotein lipase, as described above.

To complete the pathway of reverse cholesterol

Fig. 5.12 The lecithin-cholesterol acyltransferase (LCAT) reaction.

transport, HDL-cholesterol must reach the liver. There are at least two routes by which this can occur. First, the scavenger receptor SR-BI (Section 5.2.4.4) is expressed in the liver and also in steroidogenic tissues (e.g. adrenal gland and ovary). 'Docking' of HDL particles with SR-BI is followed by off-loading of their cholesteryl ester content. The cholesteryl esters enter the cellular pool and may be hydrolysed by lysosomal acid hydrolases as shown for LDL-receptor-mediated uptake (Fig. 5.8). This process is fundamentally different from the uptake of LDL particles by the LDL-receptor, however, and has been called 'selective lipid uptake'. The difference is that the particle itself is not internalized and the cholesterol-depleted particle leaves the receptor to re-enter the cycle of the HDL pathway.

The second mechanism for delivery of HDL-cholesterol to the liver brings us to an important way in which the lipoprotein pathways interact. Human plasma contains a protein known as cho-lesteryl ester transfer protein (CETP), which is secreted from the liver and from adipose tissue. CETP mediates the exchange of 'neutral lipids' (triacylglycerol and cholesteryl esters) between particles, according to concentration gradients. When HDL particles become enriched in choles-teryl esters, they may exchange these esters for triacylglycerol carried in the triacylglycerol-rich lipoproteins, i.e. chylomicrons and VLDL. Thus, chylomicrons and VLDL acquire cholesterol that stays with the particle since it is not removed by lipoprotein lipase, and it is eventually removed when the remnant particle (or LDL particle) is taken up by receptors, which, as we have seen, occurs mainly in the liver. Thus cellular cholesterol in extra-hepatic tissues, setting out for the liver in an HDL particle, may 'change vehicles' part way and end up being carried in a remnant particle. The HDL particles acquire triacylglycerol in this process and this is hydrolysed by the enzyme hepatic lipase attached to the endothelial cells lining the hepatic sinusoids. What remains is a lipid-poor HDL particle, ready to recycle via acquisition of cellular cholesterol.

5.2.6 Species differ quantitatively in their lipoprotein profiles

In some species, like man, guinea-pig and pig, lipoproteins of the LDL type (in which apolipo-protein B predominates) account for more than 50% of the total substances of density < 1.21 g ml"1. They are the LDL mammals. In the majority of mammals, however, HDL are the predominant class and may account for up to 80% of plasma substances of density < 1.21 g ml"1. Herbivorous species, with the exception of guinea-pigs, camels and rhinos, and carnivores are HDL mammals. It is worth noting that although rats are often used for the study of lipid biochemistry, their lipoprotein pattern is of the HDL type and very different from that of man. Another distinct difference is that the rat liver secretes VLDL particles that contain either apoB48 or apoB100 (whereas in humans the liver secretes only apoB100-containing particles). This almost certainly relates to the fact that their LDL-choles-terol levels are so relatively low, since apoB48-containing particles tend to be cleared from the circulation rapidly (as with chylomicrons in man). Caution needs to be exercised in extrapolating results on experimental animals to the human situation.

Whichever species one is studying, it is often necessary to quantify various aspects of the lipo-protein system. Analytical methods are summarized in Box 5.1, p. 192-3.

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