Whilst there is one major form of carbohydrate (glucose) circulating in the blood, and its concentration is relatively constant, there are various forms of fat and their concentrations may vary considerably throughout a normal day. In this section we will consider mainly the regulation of non-esterified fatty acid metabolism in the whole body, along with the fate of fat we eat in the form of triacylglycerol. The transport of triacylglycerol in the blood is closely linked with that of cholesterol, and these aspects will be considered again in more detail in Chapter 9.
Both triacylglycerol and non-esterified fatty acids are always present in the plasma and, like glucose, they are constantly turning over - being used and replaced. Non-esterified fatty acids turn over very rapidly; if an injection of a radioactively labelled fatty acid is given, the radioactivity disappears from the blood with a half-life of a few minutes. Triacylglycerol is present in various forms. The form in which it enters the blood after a meal, chylomicron-triacyl-glycerol, also has a high rate of turnover with a half-life of 5-10 minutes. Other forms of triacylglycerol in plasma have half-lives of several hours or days.
Non-esterified fatty acids enter the plasma only from adipose tissue. The process of fat mobilisation is catalysed by the enzyme hormone-sensitive lipase (Section 220.127.116.11). Thus, control of this enzyme, and of the opposing process of esterification of fatty acids in adipose tissue, has a major effect on the plasma concentration of non-esterified fatty acids. The overall rate of utilisation of non-esterified fatty acids from the plasma does not appear to be directly controlled (although it may be so in individual tissues, e.g. via activity of fatty acid transporters at the cell membrane). It depends almost entirely on the plasma concentration of non-esterified fatty acids: the higher the concentration, the higher the rate of utilisation. The relationship is close to proportional over a wide range of concentrations - i.e. utilisation of plasma non-esterified fatty acids is essentially a first-order process (Fig. 6.8). Thus, the concentration of non-esterified fatty acids in the plasma reflects their rate of release from adipose tissue, and this in turn determines the rate of non-esterified fatty acid utilisation in other tissues.
NEFA concentration (mmol/l)
NEFA concentration (mmol/l)
Fig. 6.8 Relationship between the concentration and the turnover of non-esterified fatty acids (NEFA) in plasma. Y-axis: rate of turnover of plasma non-esterified fatty acids measured by infusion of a radioactively labelled fatty acid; X-axis, plasma concentration of non-esterified fatty acids, in normal subjects who had fasted for various periods, from 14 h (left-most points) to 72 h (highest points). Based on Issekutz, B., Bortz, W.M., Miller, H.I. & Paul, P. (1967) Turnover rate of plasma FFA in humans and in dogs. Metabolism 16: 1001-1009. With the permission of W.B. Saunders Co.
Non-esterified fatty acids are not water-soluble, and they are carried in plasma bound to the plasma protein albumin. The plasma concentration of albumin is around 40 g/l and its M r (relative molecular mass) is 66 000, so the concentration is about 0.6 mmol/l. Each molecule of albumin has binding sites for around three fatty acid molecules. (These binding sites are not as specific as, for instance, a hormone receptor binding a hormone. Albumin acts as a carrier for a number of hydrophobic substances including certain drugs and the amino acid tryptophan. Non-esterified fatty acids, tryptophan and drugs compete for binding, presumably to the same sites.) Thus, about 0.6 x 3, or say 2 mmol/l of non-esterified fatty acids can be comfortably accommodated. There is always an equilibrium between fatty acids bound to albumin and a very small concentration (less than 1 |imol/l) unbound, free in solution. If the plasma concentration of non-esterified fatty acids rises above about 2 mmol/l the concentration of unbound fatty acids rises considerably, and this may have adverse effects, particularly on the heart (see Box 4.4).
The plasma non-esterified fatty acid concentration during a normal day is an inverse reflection of the plasma glucose and insulin; when the body is relatively 'starved' - for instance after overnight fast - the concentrations of glucose and insulin are at their lowest and the concentration of non-esterified fatty acids is at its highest. It can fall dramatically after a carbohydrate meal (Fig. 6.9). Situations such as exercise or illness may disturb this relationship; exercise will be considered in Chapter 7.
Triacylglycerol is also water-insoluble and is carried in the plasma in specialised particulate structures, the lipoproteins (we have already met the largest of these, the chylomicrons, which transport triacylglycerol absorbed from the
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Metabolism. There isn’t perhaps a more frequently used word in the weight loss (and weight gain) vocabulary than this. Indeed, it’s not uncommon to overhear people talking about their struggles or triumphs over the holiday bulge or love handles in terms of whether their metabolism is working, or not.