Chylomicron metabolism the exogenous pathway

The metabolism of chylomicrons is often called the exogenous pathway of lipoprotein metabolism. Exogenous means 'from outside the body', since this is the pathway for transporting fat from outside the body - in fact, fat which has been eaten. The pathway is summarised in Fig. 9.2. We have already seen how triacylglycerol and cholesterol are absorbed and re-esterified in the cells of the intestinal wall, and secreted as chylomicron particles, via the lymphatics, into the circulation (Section 3.3.3). The newly secreted chylomicron particles consist of a core of cholesteryl ester and triacylglycerol, with a surface of un-esterified cholesterol and phospholipid, and the apolipoproteins B48 and AI. There is just one molecule of apolipoprotein B48 per particle: the particle is synthesised in the enterocyte around this protein, which will stay with the particle throughout its lifetime. The particles also carry some apolipoprotein AIV, described in Section 3.2.3.2.

In the circulation, they interact with other particles, and some of the smaller apolipoproteins are passed from one particle to another, probably passively by diffusion down concentration gradients. In particular, chylomicrons rapidly acquire apolipoprotein CII, which makes them substrates for the action of lipoprotein lipase as they pass through capillaries of tissues expressing this enzyme

Box 9.2 Some important enzymes involved in lipoprotein metabolism

Lipoprotein lipase (LPL)

This enzyme is found in a number of tissues outside the liver, particularly adipose tissue, skeletal muscle and heart muscle. Its role in lipid metabolism has already been discussed (Sections 4.5.3.1 and 6.2.4.2). It is synthesised within the cells of the tissue (e.g. the adipocytes or the muscle fibres) and exported to the capillaries, where it is attached to the endothelial cells. Here it is bound (non-covalently) to highly negatively charged glycosaminoglycan chains such as heparan sulphate. LPL acts on lipoprotein particles passing through the capillaries, hydrolysing triacylglycerol molecules to release non-esterified fatty acids which may be taken up into the tissue for esterification (and hence storage - mainly in adipose tissue) or oxidation (in muscle). It can only do this if the particles contain apolipoprotein CII (see Box 9.1). LPL activity in adipose tissue is stimulated by insulin, over a relatively long time-course (a few hours). In muscle it is slightly suppressed by insulin but its activity is increased by exercise (both acutely and by training).

Hepatic lipase (HL)

This enzyme is structurally related to LPL, but has a number of different characteristics. It does not require apolipoprotein CII for activity, and it is present in the liver. It has an affinity for smaller particles than does LPL: the significance of this will be discussed below. In addition, it will hydrolyse both triacylglycerol and cholesteryl esters. HL and LPL are members of the same family as pancreatic lipase, the principal enzyme of intestinal fat digestion (Section 3.2.3.3).

Lecithin-cholesterol acyl transferase (LCAT)

This enzyme comes from the liver and is found in the plasma. It associates with particles containing apolipoprotein AI (which activates it). It transfers a fatty acid from position 2 of phosphatidylcholine (present in HDL particles) to unesterified cholesterol, forming a cholesteryl ester (see Fig. 1.6 for the structures of these species). The remaining lysophosphatidylcholine is transferred to plasma albumin from which it is rapidly removed from blood and reacylated.

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) There are two isoforms, ACAT1 and ACAT2. These are intracellular enzymes responsible for the synthesis of cholesteryl esters from cholesterol and acyl-CoA. They are responsible for esterification of dietary cholesterol within the enterocyte (for package into the chylomicron), formation of cholesteryl ester droplets for storage within cells, and providing cholesteryl esters for VLDL

secretion from the liver. ACAT1 is widely expressed, whereas ACAT2 is mainly expressed in the enterocytes of the small intestine and in the liver. There has been considerable interest in the possibility of inhibition of ACAT2 by drugs to reduce cholesterol absorption.

Fig. 9.2 The exogenous pathway of lipoprotein metabolism. Apo, apolipoprotein; FA, fatty acids; LPL, lipoprotein lipase.

such as adipose tissue and muscle. Their triacylglycerol is thus hydrolysed, and the particles shrink. At the same time, they must lose some surface coat, which they do by dissociating some unesterified cholesterol and phospholipid, and some apolipoproteins, which are taken up by other particles such as HDL.

These 'slimmed down' chylomicron particles are known as chylomicron remnants. They are relatively enriched in cholesteryl ester, since they have lost their triacylglycerol. As we will see later (Section 9.4.3), these remnants are potentially harmful if they persist in the circulation. The apolipoproteins on their surface must adopt a different conformation in the smaller particle compared with the original chylomicron, and this makes them ligands for a receptor in the liver. This is the receptor known as LRP, the LDL-receptor related

Dietary fat

Dietary fat

Chylomicrons Pathway

Fig. 9.2 The exogenous pathway of lipoprotein metabolism. Apo, apolipoprotein; FA, fatty acids; LPL, lipoprotein lipase.

protein (also known as the a2-macroglobulin receptor). Other receptors may also be involved: this is currently an area of intense research. Thus, dietary triacylglycerol is delivered to the tissues, some unesterified cholesterol enters the HDL fraction, and some triacylglycerol and cholesteryl ester is delivered, in the remnant particles, to the liver.

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Responses

  • Mike
    How is chylomicron metabolised?
    2 years ago
  • ferdinand
    How does chylomicrons pass through capillaries?
    1 year ago

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