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1.3.1.3 Metabolic strategy

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Whole body metabolic strategy comprises breaking down large macronutrient storage molecules (triacylglycerols, glycogen, protein – by lipolysis, glycogenolysis, and proteolysis respectively) into smaller energy-rich substrate molecules (NEFAs, glucose, amino acids) with distinct characteristics and roles. In the next stage of metabolism these small substrates are converted into a common fuel, acetyl-CoA (by β-oxidation, glycolysis and amino acid metabolism respectively). In the final stage of metabolism the acetyl-CoA is fully oxidised by the TCA cycle into carbon dioxide within the mitochondria. The step-wise release of energy from these pathways is carried as a hydride (H) ion by NAD+ and FAD as their reduced forms, NADH and FADH2: these redox carriers are then reoxidised by the electron transport chain, the energy derived being used to phosphorylate ADP to ATP (oxidative phosphorylation). By contrast, in anabolism these pathways are reversed, chemical energy being used to synthesise complex energy-rich storage macromolecules from simple precursor substrates (Figure 1.12).

Three key features of metabolism impact metabolic strategy and energy provision:

 Most energy stored in the body is in the form of lipid (triacylglycerols);

 This lipid cannot be converted to carbohydrate; and

 All tissues require some glucose for normal metabolic functioning, and some tissues (glycolytic, lacking mitochondria such as erythrocytes) have an absolute requirement for glucose or cannot utilise NEFAs (brain).

Since very little carbohydrate is stored (∼100 g hepatic glycogen; <1 day if it was the sole fuel), in catabolic states glucose is rapidly depleted and alternative mechanisms are required to provide or replace glucose: under these conditions breakdown of protein to amino acids, and then conversion of these to glucose by gluconeogenesis, becomes an essential pathway. Indeed, the ability of the body to divert protein from its primary (e.g. contractile) function to a secondary function of glucose provision has been the adaptation that has allowed such limited stores of the energy density- inefficient glycogen to be permitted. Another mechanism is ketogenesis, whereby the liver converts triacylglycerol-derived NEFAs into small, soluble (non-amphipathic) ketone bodies, which can be utilised by many tissues, including brain, hence acting as a ‘glucose-sparing’ substrate.

During conditions of energy repletion, energy in excess of current requirements is stored in a tissue-specific manner (lipid as triacylglycerols principally in adipose tissue; carbohydrate as glycogen in most tissues but specifically in liver for glucose release to maintain blood glucose concentration; amino acids ‘virtually’ in labile, expendable proteins, e.g. skeletal muscle contractile protein). In subsequent periods of limited energy ingestion (postabsorptive, fasted) this substrate resource can be mobilised in a regulated fashion and directed to specific tissues according to their metabolic requirement. These pathways are illustrated schematically in Figure 1.13.


Figure 1.13 Overall metabolic energy flux. The three energy groups (fats, carbohydrates, proteins) are stored in macromolecular form and can be broken down into small, monomolecular units prior to conversion to the common ‘fuel’ acetyl-CoA to be oxidised in the TCA (tricarboxylic acid) cycle – catabolism. At times of energy excess, the smaller units are assembled into the larger storage molecules – anabolism. Crucially, the conversion of pyruvate into acetyl-CoA (by pyruvate dehydrogenase) is irreversible, hence carbohydrates can be converted into fats, but fats cannot be converted into carbohydrates. 1, esterification; 2, lipolysis; 3, glycogenesis; 4, glycogenolysis; 5, protein synthesis/proteolysis; 6, lipogenesis; 7, β-oxidation; 8, gluconeogenesis; 9, glycolysis; 10, pentose phosphate pathway. Coloured arrows indicate direction of anabolic and catabolic flux, though glycolysis and gluconeogenesis do not always fit this paradigm, depending on nutritional state and particular tissue.

Overall metabolic strategy for energy provision depends on substrate fluxes within and between the three major substrate groups (Figure 1.13). Catabolism is represented as downward flux, anabolism as upward flux (though the situation is a little more complex than this, as we shall see – gluconeogenesis is active in catabolism, and glycolysis in anabolism. This is why the terms anabolism and catabolism are best reserved for the whole-body situation). Each group has a ‘storage’ macromolecule/polymer which can be broken down to individual, relatively small monomeric units in the first stage of metabolism; in the second stage of metabolism, these monomeric units are all converted into a common fuel molecule, acetyl-CoA; in the third stage of metabolism, the acetyl-CoA is completely oxidised to CO2 + H2O by the TCA cycle and electron transport chain. In intermediary metabolism it is convenient to think in terms of numbers of carbons rather than molecular weight, since carbon (C–H) represents the energy source of the substrate. Glucose (6 carbons) is stored as glycogen (hundreds of thousands of carbons). NEFAs, or ‘free’ fatty acids (typically 16 or 18 carbons) are esterified with glycerol and stored as triacylglycerols (about 60 carbons). Amino acids (typically 3–6 carbons) are not stored as an energy reserve as such but are available in reserve as proteins (again, depending on protein size, representing thousands of carbons). Acetyl-CoA comprises an acetyl group (2 carbons: CH3·CO–) attached to a carrier molecule (Coenzyme A, CoA). Oxidation of acetyl-CoA by the TCA cycle produces two CO2 molecules (i.e. the acetyl group is completely oxidised). This is highly efficient but means that acetyl-CoA cannot contribute to the dynamic pool of TCA cycle intermediates i.e. it cannot replete the intermediates of the TCA cycle as it is completely oxidised with each turn of the cycle – these must be derived from carbohydrate (>3 carbon) units. Carbohydrate metabolism yields pyruvate (3 carbons), which is next decarboxylated to acetyl-CoA (and CO2) by pyruvate dehydrogenase (PDH). PDH is essentially irreversible (far from equilibrium): acetyl-CoA cannot be converted back to pyruvate. For this reason, carbohydrates cannot be synthesised from the common fuel acetyl-CoA (Figure 1.13). Lipid metabolism comprises lipolysis of triacylglycerols to three NEFAs (+ the glycerol backbone), followed by splitting the fatty acid chain into 2-carbon units: acetyl-CoA (β-oxidation). The acetyl-CoA can be readily oxidised by the TCA cycle to provide energy but it cannot be converted to pyruvate, nor, therefore, to synthesise carbohydrates. The fatty acid chain represents an assembly of 2-carbon (acetyl-CoA-equivalent) units, and the pathway of lipogenesis utilises excess acetyl-CoA (derived from glycolysis and PDH) to synthesise fatty acids and hence triacylglycerol. Indeed triacylglycerol-fatty acid simply represents a storage form of excess acetyl-CoA (hence most fatty acids have even numbers of carbons). This means that whilst excess carbohydrate (glucose) can be readily converted to lipid (through acetyl-CoA), the reverse is not true. This is important because most stored energy is in the form of energy-dense lipid (triacylglycerol), with very little stored as glycogen, (too inefficient; <1 day supply); however, certain tissues (brain, erythrocytes, renal medulla) have an absolute requirement for glucose, and in the face of limited glycogen storage in starvation this is met by protein catabolism.

Passage of carbohydrate carbon through PDH represents an irreversible ‘gate’ through which the carbon cannot gain re-entry, committing carbohydrate to energy provision, either by immediate oxidation of acetyl-CoA, or by storage of the acetyl-CoA as lipid (fatty acid, triacylglycerol) for reconversion back to acetyl-CoA and oxidation at a later date (e.g. in subsequent starvation); this is the reason why PDH is such a highly regulated enzyme – it represents the major control point between carbohydrate and lipid metabolism (Figure 1.13).

Human Metabolism

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