Lipoprotein metabolism

Published on 01/03/2015 by admin

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Lipoprotein metabolism

The lipoprotein system evolved to solve the problem of transporting fats around the body in the aqueous environment of the plasma. A lipoprotein is a complex spherical structure that has a hydrophobic core wrapped in a hydrophilic coating (Fig 66.1). The core contains triglyceride and cholesteryl esters, while the surface contains phospholipid, free cholesterol and proteins – the apolipoproteins (Table 66.1). Cholesterol is an essential component of all cell membranes and is a precursor for steroid hormone and bile acid biosynthesis. Triglyceride is central to the storage and transport of energy within the body.

Table 66.1

Properties of some human apolipoproteins

LCAT = Lecithin; cholesterol acyl transferase.

LPL = Lipoprotein lipase.

Fig 66.1 Structure of a lipoprotein.

Nomenclature

Several different classes of lipoproteins exist whose structure and function are closely related. Apart from the largest species, the chylomicron, these are named according to their density, as they are most commonly isolated by ultracentrifugation. The four main lipoproteins and their functions are shown in Table 66.2.

Table 66.2

The four main lipoproteins and their functions

Lipoprotein	Main apolipoproteins	Function
Chylomicrons	B₄₈, A-I, C-II, E	Largest lipoprotein. Synthesized by gut after a meal. Not present in normal fasting plasma. Main carrier of dietary triglyceride
Very low density lipoprotein (VDL)	B₁₀₀, C-II, E	Synthesized in the liver. Main carrier of endogenously produced triglyceride
Low density lipoprotein (LDL)	B₁₀₀	Generated from VLDL in the circulation. Main carrier of cholesterol
High density lipoprotein (HDL)	A-I, A-II	Smallest lipoprotein. Protective function. Takes cholesterol from extrahepatic tissues to the liver for excretion

Metabolism

Lipoprotein metabolism (Fig 66.2) can be thought of as two cycles, one exogenous and one endogenous, both centred on the liver. These cycles are interconnected.

Fig 66.2 Lipoprotein metabolism.

Two key enzyme systems are involved in lipoprotein metabolism, i.e.:

Lipoprotein lipase (LPL) releases free fatty acids and glycerol from chylomicrons and VLDL into the tissues.

Lecithin: cholesterol acyl transferase (LCAT) forms cholesteryl esters from free cholesterol and fatty acids.

The exogenous lipid cycle

Dietary lipid is absorbed in the small intestine and incorporated into chylomicrons that are secreted into the lymphatics and reach the bloodstream via the thoracic duct. In the circulation, triglyceride is gradually removed from these lipoproteins by the action of lipoprotein lipase. This enzyme is present in the capillaries of a number of tissues, predominantly adipose tissue and skeletal muscle. As it loses triglyceride, the chylomicron becomes smaller and deflated, with folds of redundant surface material. These remnants are removed by the liver. The cholesterol may be utilized by the liver to form cell membrane components or bile acids, or may be excreted in the bile. The liver provides the only route by which cholesterol leaves the body in significant amounts.

The endogenous lipid cycle

The liver synthesizes VLDL particles that undergo the same form of delipidation as chylomicrons by the action of lipoprotein lipase. This results in the formation of an intermediate density lipoprotein (IDL), which becomes low density lipoprotein (LDL) when further delipidated. LDL may be removed from the circulation by the high affinity LDL receptor or by other scavenger routes that are thought to be important at high LDL levels and the main way in which cholesterol is incorported into atheromatous plaques.

HDL particles are derived from both liver and gut. They act as cholesteryl ester shuttles, removing the sterol from the peripheral tissues and returning it to the liver. The HDL is taken up either directly by the liver, or indirectly by being transferred to other circulating lipoproteins, which then return it to the liver. This process is thought to be anti-atherogenic, and an elevated HDL-cholesterol level has been shown to confer a decreased risk of coronary heart disease on an individual.

Case history 53

A 3-year-old boy with a history of chronic abdominal pain was admitted as an emergency. His blood was noted to be pink in the syringe, and the serum was milky.

Serum osmolality was measured as 282 mmol/kg and amylase 1780 U/L.

His triglyceride was reported to be >50 mmol/L.

• Why is there a discrepancy between the calculated and measured osmolality?

• What are the likely causes of the hypertriglyceridaemia?

Comment on page 169.

Apolipoproteins

Apolipoproteins are the protein components of the lipoproteins (Table 66.1). They are important in:

maintaining the structural integrity of the lipoproteins

regulating certain enzymes that act on lipoproteins

receptor recognition.

The LDL receptor (Fig 66.3), a glycoprotein present on the surface of all cells, spans the cell membrane and is concentrated in special membrane recesses, called ‘coated’ pits. It binds to lipoproteins containing apolipoprotein B and E, and internalizes them for breakdown within the cell. Receptors are then recycled to the cell surface. The number and function of receptors dictate the level of circulating LDL. When the cell has sufficient cholesterol, the synthesis of receptors is down-regulated; when the cell is cholesterol depleted, the receptors increase in number. Inherited malfunction or absence of these receptors leads to familial hypercholesterolaemia (FH).