Chapter 14 Lipids, lipoproteins and cardiovascular disease
Introduction
The major lipids present in the plasma are fatty acids, triglycerides, cholesterol and phospholipids. Other lipid-soluble substances, present in much smaller amounts but of considerable physiological importance, include steroid hormones and fat-soluble vitamins; these are discussed in Chapters 8 and 20, respectively.
Triglycerides, cholesterol and phospholipids
Because they are not water soluble, lipids are transported in the plasma in association with proteins. Albumin is the principal carrier of free fatty acids (FFAs); the other lipids circulate in complexes known as lipoproteins. These consist of a non-polar core of triglyceride and cholesteryl esters surrounded by a surface layer of phospholipids, cholesterol and proteins known as apolipoproteins (Fig. 14.1). The latter are important both structurally and in the metabolism of lipoproteins (Fig. 14.2).
Classification of lipoproteins
Lipoproteins are classified on the basis of their densities as demonstrated by their ultracentrifugal separation. Density increases from chylomicrons (CM, of lowest density) through lipoproteins of very low density (VLDL), intermediate density (IDL) and low density (LDL), to high density lipoproteins (HDL). HDL can be separated, on the basis of density, into two metabolically distinct subtypes: HDL2 (density 1.064–1.125) and HDL3 (density 1.126–1.21). Distinct subtypes of LDL (LDL-I, II and III, in increasing order of density) are also recognized. IDL are normally present in the bloodstream in only small amounts but can accumulate in pathological disturbances of lipoprotein metabolism. This classification is illustrated in Figure 14.3 and the approximate lipid and apolipoprotein content in Figure 14.4. However, it is important to appreciate that the composition of the circulating lipoproteins is not static. They are in a dynamic state with continuous exchange of components between the various types. Their principal functions are summarized in Figure 14.3 and discussed in greater detail in the next section.
Lipoprotein metabolism
Low density lipoproteins
LDLs are the principal carriers of cholesterol, mainly in the form of cholesteryl esters. LDL are formed from VLDL via IDL (Fig. 14.6). LDL can pass through the junctions between capillary endothelial cells and attach to LDL receptors on cell membranes that recognize apo B-100. This is followed by internalization and lysosomal degradation with release of free cholesterol (Fig. 14.7). Cholesterol can also be synthesized in these tissues, but the rate-limiting enzyme, HMG-CoA reductase (hydroxymethylglutaryl CoA reductase), is inhibited by cholesterol, with the result that, in the average adult, cholesterol synthesis in peripheral cells probably does not occur. Free cholesterol also stimulates its own esterification to cholesteryl ester by stimulating the enzyme acyl CoA: cholesterol acyl transferase (ACAT).
High density lipoproteins
The essential features of lipoprotein metabolism are as follows:
• dietary triglycerides are transported in chylomicrons to tissues where they can be used as an energy source or stored
• endogenous triglycerides, synthesized in the liver, are transported in VLDL and are also available to tissues as an energy source or for storage
• cholesterol synthesized in the liver is transported to tissues in LDL, derived from VLDL; dietary cholesterol reaches the liver in chylomicron remnants
• HDL acquire cholesterol from peripheral cells and other lipoproteins and this is esterified by LCAT. Cholesteryl esters are transferred to remnant particles, which are taken up by the liver, whence the cholesterol is excreted.
Reference ranges and laboratory investigations
Selection of patients for investigation
• CHD (and cerebrovascular and peripheral vascular disease)
• a family history of premature coronary disease (occurring at age <60 years)
• other major risk factors for CHD (e.g. diabetes mellitus, hypertension)
• patients with clinical features of hyperlipidaemia (see below)
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