J

K some VLDL particles \ \

Slug Life Cycle

Fig. 9.3 The endogenous pathway of lipoprotein metabolism. Particles may undergo several cycles of hydrolysis by lipoprotein lipase (LPL) in capillary beds (dashed lines), forming smaller particles which may be taken up directly by receptors in the liver; others remain in the circulation as low-density-lipoprotein (LDL) particles. These are eventually removed by uptake into tissues via the LDL receptor (Box 9.3).

Fig. 9.3 The endogenous pathway of lipoprotein metabolism. Particles may undergo several cycles of hydrolysis by lipoprotein lipase (LPL) in capillary beds (dashed lines), forming smaller particles which may be taken up directly by receptors in the liver; others remain in the circulation as low-density-lipoprotein (LDL) particles. These are eventually removed by uptake into tissues via the LDL receptor (Box 9.3).

of related small proteins.) Like the chylomicron particle and apolipoprotein B48, each VLDL particle contains just one molecule of apolipoprotein B100, which will stay with the particle throughout its lifetime. VLDL particles have a surface coat, like all lipoprotein particles, of phospholipids and unesterified cholesterol. The content of apolipoproteins E and C rapidly increases in the plasma, by transfer from other lipoproteins, mainly HDL.

VLDL particles are also substrates for lipoprotein lipase in capillary beds, and so deliver triacylglycerol from the liver to other tissues. This is a means of distributing lipid energy to the tissues. The particles may undergo several cycles of lipolysis by lipoprotein lipase as they pass again and again through tissues. As with chylomicrons, hydrolysis of the triacylglycerol core by lipoprotein li-pase leads to redundant surface material that is passed to other particles, again mainly those of the HDL fraction. The relatively cholesteryl ester-enriched particles which result have two possible fates. They may be taken up directly by a receptor in the liver and other tissues, which binds a homologous region in apolipoprotein B100 and in apolipoprotein E: it is called the LDL receptor or sometimes the B/E receptor. Thus, they deliver cholesteryl ester to tissues. Alternatively, they may remain in the circulation, having shrunk through the action of lipoprotein lipase and hepatic lipase (which becomes more important as the particles become smaller - see Box 9.2) until they have lost all surface components except apolipoprotein B100 and a shell of phospholipid and free cholesterol, and they have a core enriched in cholesteryl ester - in fact, they have become LDL particles.

9.2.2.2 LDL metabolism and regulation of cellular cholesterol content

LDL particles have a relatively long half-life in the circulation - about 3 days. During this time they are relatively stable metabolically. They leave the circulation mainly through uptake into various tissues by the LDL receptor (Box 9.3), and thus deliver cholesterol to tissues. LDL particles vary in size, a feature that will be discussed again later (Box 9.6).

As tissues take up LDL particles, the cellular cholesterol content is regulated through the SCAP-SREBP2 system (see Fig. 2.6 and Box 9.3). This means that the increase in cellular cholesterol content potentially caused by uptake of LDL-cholesterol by the LDL receptor is self-limiting.

There is an important variation on this theme. Some cells, particularly macrophages, express different receptors which will take up LDL particles. One of these alternative receptors is known as the scavenger receptor. These receptors are not subject to down-regulation like the LDL receptor, and therefore, especially in people with a high plasma LDL-cholesterol concentration, the macrophages may become excessively cholesterol-laden.

These scavenger receptors do not have a high affinity for normal LDL particles, but they bind avidly to LDL particles that have been chemically modified in various ways. In the body, this modification is probably oxidative damage to the lipids and the apolipoprotein-B100 that the particle contains. This oxida-

Box 9.3 The LDL receptor and regulation of cellular cholesterol content

The LDL receptor is a protein of Mr 120 000. It has a short intracellular domain and a long extracellular domain, terminating in the ligand-binding N-termi-nus. It is expressed in most nucleated cells, but LDL uptake is particularly active in the liver and in some tissues that need cholesterol for particular biosynthetic purposes - e.g. the adrenals and ovaries, where it serves as a precursor for steroid hormone synthesis.

LDL particles bind to the receptor, which is then internalised by endocytosis. The cholesteryl ester contained in the LDL particle is hydrolysed in the lyso-somes, liberating cholesterol, which forms part of the cellular cholesterol pool. This is used for incorporation into membranes (see Fig. 1.5), for synthesis of steroid hormones, and - in the liver - for synthesis of bile acids and formation of VLDL. The sterol content of intracellular membranes is sensed by the SCAP-SREBP2 system (Fig. 2.6), which regulates gene expression. The synthesis of new LDL receptors and of the enzymes for cholesterol synthesis, including the major regulatory enzyme, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Box 4.3), is suppressed when cellular cholesterol content is high, but stimulated by SREBP2 when cellular cholesterol is low.

Srebp2 Liver

tion may occur once LDL particles have left the plasma and entered the sub-en-dothelial space, or the intima, where there are several cell types that can cause oxidative damage. The process of uptake by scavenger receptors is presumably intended to remove the occasional 'damaged' particle, but when the number of such particles increases beyond a certain level the process becomes pathological. This is discussed in a little more detail below (Section 9.4.3 and Box 9.6).

This uptake of cholesterol-rich particles by macrophages in the arterial wall may be the beginning of the process of atherosclerosis, deposition of fatty material in the arterial wall, leading to an inflammatory process and the formation of an atherosclerotic plaque (see Section 9.4.1 for more detail).

Was this article helpful?

0 0
Get The Body Of Your Dreams

Get The Body Of Your Dreams

Everybody wants to lose weight. This is one fact that is supported by the countless weight loss programs on the market along with the numerous weight loss products, ranging from snack bars, powdered juices, shakes and even slimming soaps and lotions.

Get My Free Ebook


Post a comment