Whilst the above pathway predominates in muscle, supplying large amounts of ATP for biological work such as contraction, in liver acetyl-CoA derived from fatty acid β-oxidation is also used for ketone body synthesis (ketogenesis). Ketone bodies (acetoacetate, 3-hydroxybutyrate) are 4-carbon compounds and represent a soluble transport form of acetyl-CoA (effectively two acetyl-CoA’s joined together). This will be discussed further in Chapter 5. Acetoacetate undergoes spontaneous decarboxylation to the 3-carbon acetone: acetone probably has no physiological function in humans but is volatile and excreted in the breath with a characteristic sweet-smelling odour. (There is some evidence that acetone is converted into methylglyoxal and 1,2-propanediol, which can both act as gluconeogenic substrates, hence this is another [but also quantitatively minor] mechanism for converting lipids into carbohydrates.) Since brain cannot utilise fatty acids, the liver converts NEFAs to ketone bodies, which are exported to the brain (and other oxidative tissues such as muscle) where they are readily converted back into acetyl-CoA for oxidation in the TCA cycle and ATP production. Ketone bodies therefore constitute a major glucose-sparing fuel. Ketogenesis occurs exclusively in the liver; however, liver lacks the pathway for ketone body utilisation (ketolysis), preventing intracellular substrate cycling.
1.3.3.4 Fatty acid synthesis
The body may acquire fatty acids either from dietary fats, or it may synthesise them de novo from dietary non-lipid sources (lipogenesis). Acetyl-CoA derived from excess carbohydrates and amino acids surplus to current energy requirements is assembled into long chain fatty acids in the cytosol of lipogenic tissues such as liver and adipose tissue (and then esterified to form triacylglycerol) for energy storage. The initiating (first committed) step involves generation of malonyl-CoA (the first committed intermediate of lipogenesis, and unique to this pathway) from acetyl-CoA and bicarbonate (HCO3−) by acetyl-CoA carboxylase, and is highly regulated. The malonyl group is the donor for fatty acid synthase, a multi-catalytic polypeptide which elongates the growing fatty acid chain by 2 carbons in a repeated cycle using NADPH for energy. The fatty acid chain formed can undergo several modifications, including desaturation. The commonest fatty acids in human metabolism are palmitic (16 carbons, saturated) and oleic (18 carbons, one unsaturated bond). (This is explored further in Chapter 5, see Box 5.4.) Lipogenesis is the opposite pathway to β-oxidation, but although the chemical processes are opposite (β-oxidation: hydration, oxidation; lipogenesis: dehydration, reduction), the pathways do not utilise the same enzymes. Furthermore, lipogenesis occurs in the cytosol, whilst β-oxidation occurs in the mitochondrion, an example of intracellular compartmentation preventing substrate (futile) cycling of two opposing pathways.
The mature fatty acid is activated with CoA, forming fatty acyl-CoA, the starting point for further metabolism, by ACS (one of a family of enzymes acting on different chain length fatty acids). The primary end-point of mammalian fatty acid synthesis is palmitic acid (see Box 1.3), a 16-carbon saturated fatty acid (16:0 using the nomenclature of Box 1.3). For most cellular functions, a wide range of fatty acids is required (e.g. phospholipids formed entirely of saturated fatty acids would form very rigid membranes). Lipogenic tissues therefore also express elongase enzymes (there is a family of these: they use acetyl-CoA to add 2 carbons at a time to the carboxyl end of a fatty acid), and desaturases, which can remove hydrogen to form double-bonds. Thus, for instance, palmitic acid (16:0) can be converted to palmitoleic acid (16:1 n-7), stearic acid (18:0) and oleic acid (18:1 n-9). More details will be given later (Box 5.4).
Although the pathway of de novo lipogenesis, primarily the synthesis of fatty acids from glucose, is expressed and undoubtedly operates in human cells (adipocytes and liver; Chapter 5), it contributes only a small proportion of the fat stored in adipose tissue under most conditions – this will be discussed further in Chapter 7 (Box 7.2).
1.3.4 Protein metabolism
1.3.4.1 Pathways of amino acid metabolism
Amino acids may be synthesised, obtained from the diet or derived from proteolysis (although no dedicated protein exists whose sole function is simply to supply amino acids for energy). ‘Non- essential’ amino acids can be synthesised from intermediary metabolites (or from other amino acids); ‘essential’ amino acids cannot be synthesised by humans and therefore must be obtained from the diet. ‘Conditionally essential’ amino acids can be synthesised in only limited amounts, and this must be supplemented by the diet in states of rapid protein synthesis (e.g. growth). Free amino acids constitute a soluble amino acid substrate pool; this is quantitatively small, but dynamic, turning over rapidly. From this pool, amino acids are used for biosynthetic functions as well as degradation for energy production, their carbon skeletons entering the common metabolic pool of intermediary metabolites shared with carbohydrate and lipid metabolism. Dietary amino acids surplus to synthetic requirements (for proteins, nucleotides, hormones, neurotransmitters, creatine, porphyrins etc.) are utilised directly for energy production. Some tissues (e.g. liver, intestine, leukocytes) preferentially oxidise amino acids for energy. Amino acids contain approximately the same energy as carbohydrates – about half that of lipids. Amino acids may be used to provide metabolic energy either (i) in the well-fed state, when amino acid intake exceeds protein synthesis requirement, in which case excess exogenous amino acids are oxidised or stored as non-protein energy reserve, or (ii) in starvation, when endogenous amino acids derived from ‘dispensable’ protein are oxidised for energy.
Whilst amino acids are used to synthesise proteins, most proteins are not inert but are constantly broken down (proteolysis) to amino acids and re-synthesised (protein synthesis), this constituting the protein turnover rate: this cycling varies between individual proteins. For a protein to be useful as a source of amino acids for energy production, its turnover rate must be relatively high, and there must be a relatively large amount of it in the body (and it must be, at least in part, expendable). The rate of protein turnover depends on the individual protein – generally, gastrointestinal and hepatic proteins turn over rapidly (5–15% per day) whilst skeletal muscle contractile protein turnover is relatively slow (∼2% per day) (see Chapter 7 for more detail); however, because of the large mass of skeletal muscle, and the ability to maintain viability despite loss of >50% of actin and myosin, this depot makes the largest contribution to whole body protein turnover, and hence amino acid availability for metabolism and energy release.
Typical dietary protein intake is ∼100 g d−1 (with the same amount excreted as nitrogen- equivalent), whilst the ∼10 kg of body protein is turned over to ∼100 g of free amino acids at a turnover rate of ∼300 g d−1. Dietary proteins are digested in the small intestine and absorbed as free amino acids and short peptides (see Chapter 4, Section 4.3.2). Enterocytes of the small intestine remove some amino acids, especially glutamine, for use as an oxidative fuel (see Chapter 5.8). The remaining products of digestion enter the portal vein and then the liver, where further preferential amino acid extraction occurs (most are extracted by the liver). Amino acid oxidation is, under most circumstances, the major oxidative pathway in the liver – about 60% of incoming amino acids may be directed into immediate oxidation. The rate of hepatic protein synthesis is also high, and since much of the protein is secreted (e.g. albumin), this represents a net loss of amino acids from the liver (perhaps a further 20% of the incoming amino acids). The remaining mixture of amino acids, around 20% of those absorbed, enters the systemic