HDL metabolism

Whilst LDL particles regulate the cholesterol content of cells by delivering cholesterol, HDL particles bring about the opposite process - the removal of cholesterol, which is transported to the liver for ultimate excretion.

9.2.3.1 HDL and reverse cholesterol transport

HDL particles begin their life as apolipoprotein AI molecules secreted from the liver and intestine, associated with some phospholipid. These nascent particles are called pre-$ HDL from their migration pattern on electrophoresis. As they acquire phopholipids and cholesterol, they form disc-shaped molecular aggregates, so-called discoidal HDL. Nascent HDL acquire cholesterol in two ways. First, they interact with cells and collect excess cellular cholesterol. Secondly, they acquire the excess surface material released during the lipolysis of the tri-acylglycerol-rich lipoproteins by lipoprotein lipase (Sections 9.2.1, 9.2.2). The unesterified cholesterol that is acquired by these routes is esterified to a long-chain fatty acid by the action of the enzyme LC AT associated with HDL particles (Box 9.2), which is activated by apolipoprotein AI. Thus, the particles acquire a core of hydrophobic cholesteryl esters, and 'mature' into spherical, cholesterol-rich particles. These larger, cholesterol-rich particles can be sub-fractionated by ultracentrifugation into HDL2 (larger particles) and HDL3 (smaller). The larger particles give up their cholesterol to the liver, both by interaction with specific receptors, and indirectly by transferring cholesteryl ester to the triacylglycerol-rich lipoproteins for return to the liver (this mechanism is discussed further below in Section 9.2.3.2). The smaller HDL particles and relatively lipid-poor apolipoprotein AI resulting are then ready to accept further cholesterol from peripheral tissues. Thus, there is a constant recycling of HDL particles between smaller, cholesterol-depleted and larger, cholesterol-rich forms (Fig. 9.4).

The interaction of HDL particles with cells has recently been understood in molecular detail. HDL particles acquire cellular cholesterol by interacting with a membrane-associated protein that is a member of a large family of proteins with the ability to bind ATP on their cytoplasmic domain. This particular ATP-binding motif gives them the name of ATP-binding cassette or ABC proteins. The one involved with transfer of cholesterol to HDL is known as ABC-A1. It transfers cholesterol from cell membranes to HDL. Note that the action of LCAT associated with HDL is essential to this process: by esterifying cholesterol, it maintains the concentration gradient so that more cholesterol can be taken up by the particle. At the hepatocyte, mature HDL particles interact with

Lcat Membrane Domain

Fig. 9.4 HDL metabolism. Pre-P HDL is apolipoprotein AI (apoAl) associated with some phospholipid. It acquires free cholesterol (FC) and further phospholipid (PL) by interaction with cells and forms discoidal HDL particles, which acquire further FC and PL that is shed from triacylglycerol-rich lipoprotein (TRL) particles as lipoprotein lipase (LPL) acts upon them. Lecithin-cholesterol acyltransferase (LCAT) esterifies the FC the HDL particles have acquired and by this means they mature into spherical, cholesterol-rich HDL2 particles. These may give up their cholesterol and some phospholipid to the liver from where the cholesterol can be excreted in the bile. The lipid-poor apolipoprotein AI is thereby regenerated and begins the cycle again. Based on Fielding, P.E. & Fielding, C.J. (1996) Dynamics of lipoprotein transport in the human circulatory system. In: Biochemistry of Lipids, Lipoproteins and Membranes (eds Vance, D.E. & Vance, J.E.), 495-516. With permission of Elsevier Science.

Fig. 9.4 HDL metabolism. Pre-P HDL is apolipoprotein AI (apoAl) associated with some phospholipid. It acquires free cholesterol (FC) and further phospholipid (PL) by interaction with cells and forms discoidal HDL particles, which acquire further FC and PL that is shed from triacylglycerol-rich lipoprotein (TRL) particles as lipoprotein lipase (LPL) acts upon them. Lecithin-cholesterol acyltransferase (LCAT) esterifies the FC the HDL particles have acquired and by this means they mature into spherical, cholesterol-rich HDL2 particles. These may give up their cholesterol and some phospholipid to the liver from where the cholesterol can be excreted in the bile. The lipid-poor apolipoprotein AI is thereby regenerated and begins the cycle again. Based on Fielding, P.E. & Fielding, C.J. (1996) Dynamics of lipoprotein transport in the human circulatory system. In: Biochemistry of Lipids, Lipoproteins and Membranes (eds Vance, D.E. & Vance, J.E.), 495-516. With permission of Elsevier Science.

a receptor that is a member of a large family of receptors known as scavenger receptors, because their role is generally to remove 'debris' by phagocytosis (especially in macrophages). This particular receptor is known as scavenger receptor (SR)-BI and 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 hydrolases as shown for LDL-receptor mediated uptake (Box 9.3). 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 internalised and the cholesterol-depleted particle leaves the receptor to re-enter the cycle of the HDL pathway.

By these means, excess cholesterol is transferred from peripheral tissues to the liver, from where it can be excreted as cholesterol and as bile salts in the bile (see Boxes 3.1 and 9.4). This process of removal of cholesterol from the tissues, transport to the liver and ultimate excretion from the body is the opposite of the delivery of cholesterol by LDL: it is known as reverse cholesterol transport (Fig. 9.5).

Box 9.4 Cholesterol homeostasis in the body

The body pool of cholesterol is about 140 g. Of this, about 8 g is present in the plasma, mainly in LDL.

About 1 g of cholesterol enters the body pool each day, 400 mg from intestinal absorption and 600 mg from biosynthesis; i.e. there is < 1% turnover per day of the body cholesterol pool. Note that this does not conflict with the figure of 1 g per day of cholesterol in the diet given in Table 3.1 since cholesterol absorption is incomplete.

There is a turnover of about 5 g plasma cholesterol/day, cholesterol entering the plasma in chylomicrons and VLDL particles, and from tissues into HDL, and leaving in the form of chylomicron-remnants, VLDL particles, LDL particles and by removal from HDL.

There is also turnover of cholesterol in the enterohepatic circulation (see Box 3.1). Bile salts, formed from cholesterol in the liver, are secreted in the bile and largely reabsorbed in the ileum. The total pool of 2.5-4 g of bile acids is recycled about twice with each meal, i.e. the turnover is rapid: about 18 g/day leaves in the bile and most of this (approximately 17.5 g) is reabsorbed. Cholesterol is also secreted in the bile, about 1 g/day; of this, about half is reabsorbed and the remainder lost in the faeces. The net loss of cholesterol and bile acids is around 1 g/day, matching input from diet and synthesis.

The enterohepatic circulation may be interrupted by a resin such as cholestyramine or cholestipol which binds the bile acids, prevents their re-absorption and leads to their excretion in faeces. More cholesterol is converted to bile acids to keep the total amount constant. If completely efficient, this treatment could lead to the loss of about 18 g of cholesterol each day - many times the normal turnover rate of the body cholesterol pool. It can thus help to lower the plasma cholesterol concentration. However, the powerful feedback control of cellular cholesterol content on HMG-CoA reductase will minimise its effect.

Data for this box taken from Newsholme & Leech (1983), Hunt & Groff (1990) and Lewis (1990).

9.2.3.2 Cholesteryl ester transfer protein

A circulating protein known as cholesteryl ester transfer protein (CETP) catalyses the exchange of hydrophobic lipids - cholesteryl esters and triacyl-glycerol - between lipoprotein particles (Fig. 9.5). They exchange by facilitated diffusion along concentration gradients. When the plasma concentration of triacylglycerol is high - for instance, after a meal when triacylglycerol-laden chylomicrons are present - CETP will catalyse the exchange of cholesteryl ester from HDL to triacylglycerol-rich lipoproteins, whilst triacylglycerol moves in the opposite direction. The cholesteryl esters remain with the triacylglycerol-rich lipoprotein particle until it is taken up by the liver as a remnant. The HDL

Forward cholesterol transport

Tissues'

Synthesis

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