Human Metabolism. Keith N. Frayn

influences: it cannot, therefore, be in the form of simple sugars or even oligosaccharides, because of the osmotic problem this would cause to the cells. This is overcome by the synthesis of the macromolecule glycogen, so that the osmotic effect is reduced by a factor of many thousand compared with monosaccharides. The synthesis of such a polymer from glucose, and its breakdown, are brought about by enzyme systems which are themselves regulated, thus giving the opportunity for precise control of the availability of glucose.

      4 Glycogen in an aqueous environment (as in cells) is highly hydrated; in fact, it is always associated with about three times its own weight of water. Thus, storage of energy in the form of glycogen carries a large weight penalty (discussed further in Chapter 7).

      1.2.2.2 Fats

      Just as there are many different sugars and carbohydrates built from them, so there are a variety of types of fat. The term fat comes from Anglo-Saxon and is related to the filling of a container or vat. The term lipid, from Greek, is more useful in chemical discussions since ‘fat’ can have so many shades of meaning. Lipid materials are those substances which can be extracted from tissues in organic solvents such as petroleum or chloroform. This immediately distinguishes them from the largely water-soluble carbohydrates.

      Among lipids there are a number of groups (Figure 1.4). The most prevalent, in terms of amount, are the triacylglycerols or triglycerides, referred to in older literature as ‘neutral fat’ since they have no acidic or basic properties. These compounds consist of three individual fatty acids, each linked by an ester bond to a molecule of glycerol. As discussed above, the triacylglycerols are very non-polar, hydrophobic compounds. The phospholipids are another important group of lipids – constituents of membranes and also of the lipoprotein particles which will be discussed in Chapter 10. Steroids – compounds with the same nucleus as cholesterol (Figure 1.6) – form yet another important group and will be considered in later chapters, steroid hormones in Chapter 6 and cholesterol metabolism in Chapter 10.

      Fatty acids are the building blocks of lipids, analogous to the monosaccharides. The fatty acids important in metabolism are mostly unbranched, long-chain (12 carbon atoms or more) carboxylic acids with an even number of carbon atoms. They may contain no double bonds, in which case they are referred to as saturated fatty acids, one double bond (mono-unsaturated fatty acids), or several double bonds – the polyunsaturated fatty acids. Many individual fatty acids are named, like monosaccharides, according to the source from which they were first isolated. Thus, lauric acid (C12, saturated) comes from the laurel tree, myristic acid (C14, saturated) from the Myristica or nutmeg genus, palmitic acid (C16, saturated) from palm oil, and stearic acid (C18, saturated) from suet, or hard fat (Greek στέαρ [steatos]). Oleic acid (C18, mono-unsaturated) comes from the olive (from Latin: olea, olive, or oleum, oil). Linoleic acid (C18 with two double bonds) is a polyunsaturated acid common in certain vegetable oils; it is obtained from linseed (from the Latin linum for flax and oleum for oil).

      The fatty acids mostly found in the diet have some common characteristics. They are composed of even numbers of carbon atoms, and the most abundant have 16 or 18 carbon atoms. There are three major series or families of fatty acids, grouped according to the distribution of their double bonds (Box 1.3).

Box 1.3 The structures and interrelationships of fatty acids

      In the orthodox nomenclature, the position of double bonds is counted from the carboxyl end. Thus, α-linolenic acid (18 carbons, 3 double bonds) may be represented as cis-9,12, 15-18:3, and its structure is:

(where the superscripts denote the numbering of carbon atoms from the carboxyl end). However, this is also known as an n-3 (or sometimes as an ω-3) fatty acid, since its first double bond counting from the non-carboxyl (ω) end is after the third carbon atom. On the latter basis, unsaturated fatty acids can be split into three main families, n-3, n-6, and n-9 (Table 1.3.1).

      The saturated fatty acids can be synthesised within the body. In addition, many tissues possess the desaturase enzymes to form cis-6 or cis-9 double bonds, and to elongate the fatty acid chain (elongases) by addition of two-carbon units at the carboxyl end. (These steps are covered in more detail in Box 5.4) But these processes do not alter the position of the double bonds relative to the ω end, so fatty acids cannot be converted from one family to another: an n-3 fatty acid (for instance) remains an n-3 fatty acid. Oleic acid (cis-9-18:1, n-9 family) can be synthesised in the human body, but we cannot form n-6 or n-3 fatty acids. Since the body has a need for fatty acids of these families, they must be supplied in the diet (in small quantities). The parent members of these families that need to be supplied in the diet are linoleic acid for the n-6 family and α-linolenic acid for the n-3 family. These are known as essential fatty acids. They can be converted into other members of the same family, although there seem to be health benefits of consumption of other members of the n-3 family, particularly 20:5 n-3 (eicosapentaenoic acid) and 22:6 n-3 (docosahexaenoic acid), found in high concentrations in fish oils. This is discussed further in Box 10.5. Some patients receiving all their nutrition intravenously have become deficient in essential fatty acids. The problem may be cured by rubbing sunflower oil into the skin!

Table 1.3.1

Family	Source	Typical member	Simplified structure
Saturated	Diet or synthesis	Myristic	14:0
		Palmitic	16:0
		Stearic	18:0
n-9	Diet or synthesis	Oleic	9-18:1
n-6	Diet	Linoleic	9,12-18:2
n-3	Diet	α-linolenic	9,12,15-18:3

      Differences in the metabolism of the different fatty acids are not very important from the point of view of their roles as fuels for energy metabolism. When considering the release, transport and uptake of fatty acids (not part of triacylglycerols), the term non-esterified fatty acids (NEFAs) will therefore be used without reference to particular molecular species. In a later section (Box 10.5) some