Plasma Lipids and Lipoproteins
Lipids play a critical role in almost all aspects of biological life – they are structural components in cells and are involved in metabolic and hormonal pathways. The importance of having a knowledge of lipid disorders cannot be overstated, not least because they are common in clinical practice and, in some cases associated with atherosclerosis such as coronary heart disease, one of the biggest killers in urbanized societies.
Lipids are defined as organic compounds that are poorly soluble in water but miscible in organic solvents. Lipidology is the study of abnormal lipid metabolism. An understanding of the pathophysiology of plasma lipid metabolism is usefully based on the concept of lipoproteins, the form in which lipids circulate in plasma.
PLASMA LIPIDS
The chemical structures of the four main forms of lipid present in plasma are illustrated in Figure 13.1.
 Figure 13.1 Lipid structures. P, phosphate; N, nitrogenous base; R, fatty acid. |
FATTY ACIDS
These are straight-chain carbon compounds of varying lengths. They may be saturated, containing no double bonds, monounsaturated, with one double bond, or polyunsaturated, with more than one double bond (Table 13.1).
Fatty acids can esterify with glycerol to form triglycerides or be non-esterified (NEFAs) or free. Plasma NEFAs liberated from adipose tissue by lipase activity are transported to the liver and muscle mainly bound to albumin. The NEFAs provide a significant proportion of the energy requirements of the body. Summary diagrams of fatty acid synthesis and oxidation are shown in Figures 13.2 and 13.3.
Triglycerides are transported from the intestine to various tissues, including the liver and adipose tissue, as lipoproteins. Following hydrolysis, fatty acids are taken up, re-esterified and stored as triglycerides. Plasma
triglyceride concentrations rise after a meal, unlike that of plasma cholesterol.
triglyceride concentrations rise after a meal, unlike that of plasma cholesterol.
Table 13.1 Some of the major fatty acids found in the plasma | ||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Phospholipids are complex lipids, similar in structure to triglycerides but containing phosphate and a nitrogenous base in place of one of the fatty acids. They fulfil an important structural role in cell membranes, and the phosphate group confers solubility on nonpolar lipids and cholesterol in lipoproteins.
A family of nuclear receptors that are activated by fatty acids – called peroxisome proliferator-activated receptors (PPARs) – has been described and implicated in insulin resistance and dyslipidaemia. The PPARs can be subdivided into α-PPARs, which are activated by fibrate drugs, and γ-PPARs, which are activated by thiazolidinedione drugs, for example pioglitazone or rosiglitazone.
CHOLESTEROL
Cholesterol is a steroid alcohol found exclusively in animals and present in virtually all cells and body fluids. It is a precursor of numerous physiologically important steroids, including bile acids and steroid hormones. A summary of the cholesterol synthetic pathways is shown in Figure 13.4. The rate-limiting enzyme is 3-hydroxy- 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which is controlled by negative feedback by the intracellular concentration. About two-thirds of the plasma cholesterol is esterified with fatty acids to form cholesterol esters.
LIPOPROTEINS
Because lipids are relatively insoluble in aqueous media, they are transported in body fluids as, often spherical,
soluble protein complexes called lipoproteins. Lipids can be derived from food (exogenous) or synthesized in the body (endogenous). The water-soluble (polar) groups of proteins, phospholipids and free cholesterol face outwards and surround an inner insoluble (nonpolar) core of triglyceride and cholesterol esters.
soluble protein complexes called lipoproteins. Lipids can be derived from food (exogenous) or synthesized in the body (endogenous). The water-soluble (polar) groups of proteins, phospholipids and free cholesterol face outwards and surround an inner insoluble (nonpolar) core of triglyceride and cholesterol esters.
 Figure 13.2 Summary of fatty acid synthesis and adipose tissue substrates. Reproduced with kind permission from Candlish JK and Crook M. Notes on Clinical Biochemistry. Singapore: World Scientific Publishing, 1993. |
 Figure 13.3 Summary of fatty acid oxidation. CoA, coenzyme A. Reproduced with kind permission from Candlish JK and Crook M. Notes on Clinical Biochemistry. Singapore: World Scientific Publishing, 1993. |
 Figure 13.4 Summary of pathways of cholesterol synthesis. CoA, coenzyme A. Reproduced with kind permission from Candlish JK and Crook M. Notes on Clinical Biochemistry. Singapore: World Scientific Publishing, 1993. |
Lipoproteins are classified by their buoyant density, which inversely reflects their size. The greater the lipid to protein ratio, the larger their size and the lower the density. Lipoproteins can be classified into five main groups (Table 13.2). The first three are triglyceride rich and, because of their large size, they scatter light, which can give plasma a turbid appearance (lipaemic) if present in high concentrations:
Table 13.2 Characteristics of major lipoproteins | ||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
Chylomicrons are the largest and least dense lipoproteins and transport exogenous lipid from the intestine to all cells.
Very low-density lipoproteins (VLDLs) transport endogenous lipid from the liver to cells.
The other two lipoprotein classes contain mainly cholesterol and are smaller in size:
Low-density lipoproteins are formed from VLDLs and carry cholesterol to cells.
If a lipaemic plasma sample, for example after a meal, is left overnight at 4°C, the larger and less dense chylomicrons form a creamy layer on the surface. The smaller and denser VLDL and IDL particles do not rise, and the sample may appear diffusely turbid. The LDL and HDL particles do not contribute to this turbidity because they are small and do not scatter light. Fasting plasma from normal individuals contains only VLDL, LDL and HDL particles.
In some cases of hyperlipidaemia, the lipoprotein patterns have been classified (Fredrickson’s classification) according to their electrophoretic mobility. Four principal bands are formed, based on their relative positions, by protein electrophoresis, namely α (HDL), pre-β (VLDL), β (LDL) and chylomicrons (Table 13.3).
Table 13.3 Fredrickson’s classification of hyperlipidaemias | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||
Intermediate-density lipoproteins in excess may produce a broad β-band. Some individuals with hyperlipidaemia may show varying electrophoretic patterns at different times.
Ultracentrifugation (separation based upon particle buoyant density) or electrophoretic techniques are rarely used in routine clinical practice as these may require completed apparatus and experienced operators. Instead, the lipoprotein composition of plasma may be inferred from standard clinical laboratory lipid assays. As fasting plasma does not normally contain chylomicrons, the triglyceride content reflects VLDL. Furthermore, generally about 70 per cent of plasma cholesterol is incorporated as LDL and 20 per cent as HDL. The latter particles, because of their high density, can be quantified by precipitation techniques that can assay their cholesterol content by subtraction, although direct HDL assays are now often used.
The Friedewald equation enables plasma LDL cholesterol concentration to be calculated and is often used in clinical laboratories:
This equation makes certain assumptions, namely that the patient is fasting and the plasma triglyceride concentration does not exceed 4.5 mmol/L (otherwise chylomicrons make the equation inaccurate).
There has been recent interest in the subdivision of LDL particles into small dense LDL2 and LDL3, which appear to be more atherogenic and more easily oxidized than the larger LDL1 particles. Additionally, another lipoprotein called lipoprotein (a), or Lp(a), has been found. This is similar in lipid composition to LDL but has a higher protein content. One of its proteins, called apolipoprotein (a), shows homology to plasminogen and may disrupt fibrinolysis, thus evoking a thrombotic tendency. The plasma concentration of Lp(a) is normally less than 0.30 g/L and it is thought to be an independent cardiovascular risk factor.
The proteins associated with lipoproteins are called apolipoproteins (apo). ApoA (mainly apoA1 and apoA2) is the major group associated with HDL particles. The apoB series (apoB100) is predominantly found with LDL particles and is the ligand for the LDL receptor. Low-density lipoprotein has one molecule of apoB100 per particle. Some reports have suggested that the plasma apoA1 to apoB ratio may be a useful measure of cardiovascular risk (increased if the ratio is less than 1) and it is not significantly influenced by the fasting status of the patient. The apoC series is particularly important in triglyceride metabolism and, with the apoE series, freely interchanges between various lipoproteins. Some of the functions of these apolipoproteins are described in Table 13.4.
Lipoprotein-associated phospholipase A2 [also called platelet-activating factor acetylhydrolase (PAFAH)] is present mainly on LDL and to a lesser degree HDL. It is produced by inflammatory cells and is involved in atherosclerosis formation and levels are associated with increased risk of coronary artery disease and stroke.
Table 13.4 The main apolipoproteins and their common functions | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||
??
from chylomicron remnants via the exogenous pathway or synthesized locally. These lipids are transported from the liver as VLDL.
from chylomicron remnants via the exogenous pathway or synthesized locally. These lipids are transported from the liver as VLDL.
 |
Very low-density lipoprotein is a large triglyceriderich particle consisting also of apoB100, apoC and apoE. Following hepatic secretion, it incorporates additional apoC from HDL particles within the circulation. Like chylomicrons, VLDL is hydrolysed by lipoprotein lipase in the peripheral tissues, albeit more slowly. The resulting VLDL remnant or IDL contains cholesterol and triglyceride as well as apoB and apoE and is rapidly taken up by the liver or converted by the action of hepatic lipase to LDL by losing apoE and triglyceride.
Low-density lipoprotein is a small cholesterol-rich lipoprotein containing only apoB. It represents about 70 per cent of the total plasma cholesterol concentration. It can be taken up by most cells, although mainly the liver by the LDL or B/E receptor which recognizes and binds apoB100. Within the cell, the LDL particles are broken down by lysosomes, releasing cholesterol. This cholesterol can be incorporated into cell membranes or in specific tissues such as the adrenal cortex or gonads and utilized in steroid synthesis.
Most cells are able to synthesize cholesterol, but, to avoid intracellular accumulation, there is a feedback control system reducing the rate of synthesis of the LDL receptors. Although most of the plasma LDL is removed by LDL receptors, if the plasma cholesterol concentration is excessive, LDL particles, by virtue of their small size, can infiltrate tissues by passive diffusion and can even cause damage, as in atheroma formation within arterial walls. An alternative route of removal of LDL is via the reticuloendothelial system, collectively termed the scavenger cell pathway, which recognizes only chemically modified LDL, for example oxidized LDL.
The liver has a central role in cholesterol metabolism:
it contains most of the LDL receptors,
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
