BASIC SCIENCE

Human metabolism: chemical reactions throughout the cell that would not occur
without external energy input, because they are energetically

pathways and clinical unfavourable. Besides carrying energy in metabolic pathways,

the cellular energy charge and redox potential are major regu-

aspects lators of metabolism.

Energy substrates
Rhys D Evans
Energy is derived from three groups of energy-rich compounds:
Lisa C Heather carbohydrates, lipid (fats) and proteins (amino acids) (Figure 1).
Carbohydrates (hydrated carbon: C(H2O)n) are soluble, fast and
easy to transport, relatively non-toxic, and can yield some energy
Abstract anaerobically in hypoxia or ischaemia when oxygen availability
Metabolism describes the series of chemical reactions that are con- is limited. However, their water solubility means that in storage
cerned with the provision of energy to biological systems. They may form as glycogen they retain significant amounts of water; in
be divided into reactions involved in energy yield (catabolism: demand addition, carbohydrates are partially oxidized and hence do not
exceeds supply), and energy storage (anabolism: supply exceeds contain as much energy as lipids. Therefore only limited amounts
demand). Regulation of these pathways is critical for homeostasis, are stored. By contrast, lipids are highly reduced and very
and derangements in metabolism are seen in a wide variety of patho- energy-dense, hence they function as the principal energy store
logical processes. Understanding metabolism is key to the treatment for free-living animals and are major energy providers to most
of many diseases, notably diabetes, as well as underpinning clinical tissues. However, their water-insolubility makes lipids slow to
nutritional support. mobilize, and unlike carbohydrates they cannot yield energy
Keywords Carbohydrates; diabetes; lipids; metabolism; proteins anaerobically, so cannot be used by erythrocytes and renal me-
dulla. Furthermore, they cannot cross the bloodebrain barrier so
cannot be used by the CNS. Because lipids are more reduced,
The word metabolism is derived from the Greek ‘to change’, and relatively more oxygen is required to extract energy from them
describes the series of biochemical reactions that provide the (2.8 ATP/O2) compared to carbohydrates (3.7 ATP/O2) and this
body with the energy it requires to maintain biological functions may be critical in high work-load/oxygen-challenged tissues
(e.g. biosynthesis, maintenance of ionic gradients, muscle such as myocardium and exercising skeletal muscle. Also, lipids
contraction, heat generation). This energy must ultimately be in the form of non-esterified fatty acids are amphipathic (deter-
derived from food. The rate of energy production measured gent-like) and hence disruptive to membranes and potentially
under basal conditions e ‘basal metabolic rate’ (BMR) e is toxic. Amino acids have similar energy yields to carbohydrates,
affected by many factors, including muscle contraction, food and most can be converted to glucose. Under conditions of
ingestion, size, gender, age, temperature, sepsis, cancer and carbohydrate depletion (e.g. starvation) certain proteins can be
several hormones, including thyroid hormones and catechol- broken down to yield amino acids for conversion into carbohy-
amines. The metabolic rate can be estimated by measuring drates to supply glucose-dependent tissues. Although proteins
oxygen consumption (VO2; indirect calorimetry). are not stored specifically to supply energy, they act as a virtual
The process of converting excess energy-rich substrate pre- carbohydrate supply in catabolic states of carbohydrate exhaus-
cursors in food into complex energy storage molecules is termed tion (e.g. starvation).
anabolism, whereas the process degrading substrates to mobilize Metabolism of the three major substrate groups converges at a
biologically useable energy is termed catabolism. Imbalance of common intermediate, acetyl-CoA, in mitochondria (Figure 1).
these pathways leads to cachexia or obesity. Tissues have Acetyl-CoA can enter the tricarboxylic acid (TCA; Krebs) cycle
specialized metabolic functions (e.g. adipose tissue stores sub- and be completely oxidized to 3 NADH, 1 FADH2, 1 GTP and 2
strate, muscle oxidizes substrate, lactating mammary gland CO2. The hydride carriers convey electrons to the electron
exports substrate). The liver is a metabolic ‘transformer’ that transport chain in the presence of oxygen, and result in the
regulates substrate supply between tissues, and pancreas detects generation of large amounts of ATP via oxidative phosphoryla-
and signals nutritional status. tion (and H2O).
Metabolic energy is carried in two main forms: (i) ‘high Pancreas is the key organ detecting metabolic status.
energy’ phosphate groups including ATP, GTP and creatine Pancreatic b-cells sense high blood glucose and release insulin in
phosphate; and (ii) hydride ion (effectively, electron) carriers response. Pancreatic a-cells release glucagon in response to low
such as NADH, FADH2 and NADPH. These molecules are used in blood glucose concentration. Carbohydrate and lipid utilization
are reciprocally related (Randle cycle), a mechanism partly
orchestrated by insulin.

Rhys D Evans MD DPhil is Reader in Metabolic Biochemistry,

Carbohydrate metabolism
Department of Physiology, Anatomy, and Genetics, University of
Oxford, Oxford, UK. Conflicts of interest: none declared. Carbohydrate metabolism centres around the hexose sugar
Lisa C Heather BSc DPhil is Associate Professor in Metabolic glucose (C6H12O6). Following uptake into the cell by glucose
Biochemistry, Department of Physiology, Anatomy, and Genetics, transporters (GLUT), glucose is rapidly phosphorylated to
University of Oxford, Oxford, UK. Conflicts of interest: none declared. glucose-6-phosphate (G6P) by the enzyme hexokinase (liver and

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 BASIC SCIENCE

Energy provision by the three key substrate classes

TRIGLYCERIDE GLYCOGEN PROTEIN

Lipid Lipolysis Glycogenesis Glycogenolysis

esterification

free fatty acids glucose Pentose

glucogenic ketogenic
phosphate amino acids amino acids
pathway
Gluconeogenesis
Glycolysis

lactate pyruvate

CO2
-oxidation

Lipogenesis acetyl-CoA
Ketolysis

ketone bodies
CoA Ketogenesis
Electron NADH/ e- HMG-CoA
O2 Transport Chain e- FADH 2 TCA
cycle
H 2O cholesterol
ATP ADP NAD +/
FAD CO2
WORK

In catabolism, large storage macromolecules are broken down to intermediate substrates before
conversion to acetyl-CoA, the common fuel for TCA (tricarboxylic acid) cycle in the mitochondrion.
Acetyl-CoA is oxidized to carbon dioxide and energy yield used in the electron transport chain to
produce ATP. Under conditions of energy excess (anabolism), large macromolecules are synthesized
for energy storage.

Figure 1

pancreas: glucokinase); G6P is a central hub in carbohydrate hours, whereas skeletal muscle stores about 350 g of glycogen,
metabolism and can be used for glycolysis and glycogen syn- sufficient for about 70 minutes of muscle contraction.
thesis (glycogenesis), but it may also be derived from glycogen
breakdown (glycogenolysis) and from non-carbohydrate pre- Glycolysis
cursors (gluconeogenesis), depending on tissue and prevailing Glucose is cleaved into pyruvate by glycolysis in the cytosol of all
metabolic state. cells (Figure 2), and generates energy without the use of oxygen.
One molecule of glucose yields two molecules of pyruvate, 2
Glycogen NADH and 2 ATP, the latter via substrate level phosphorylation.
Carbohydrate is stored in limited amounts as cytoplasmic Pyruvate can be imported into the mitochondria and decar-
glycogen granules in most tissues, as an energy resource available boxylated to acetyl CoA (see Figure 1), remain in the cytosol and
within the tissue (and hence independent of blood supply) for be reduced to lactate, or be transaminated to the amino acid
rapid utilization when required. Glycogen is a polymer of alanine. Its fate is determined by the tissue, oxygen availability
glucose that glycogen synthase assembles into a linear chain, but and circulating hormones. Hence, in muscle, glycolysis splits
every 8e10 glucose residues a branch point is introduced. This glucose in order to provide energy (pyruvate completely oxidized
produces a highly branched tree-like structure with many free to CO2 via acetyl-CoA), but in liver, excess glucose is broken
(‘non-reducing’) ends, which enables rapid glucose release during down by glycolysis to pyruvate, then acetyl-CoA, and used for
glycogenolysis by the enzyme glycogen phosphorylase. In tissues lipid synthesis (see Figure 1). Glycolysis is tightly regulated by
which store glycogen for their own utilization (e.g. muscle), the hormonal and metabolic signals and is linked to the energy status
G6P generated by glycogenolysis undergoes glycolysis for energy of the cell via allosteric effects of AMP, ATP and citrate.
production; however, in liver the G6P is dephosphorylated by
glucose-6-phosphatase into free glucose, which is released into the Gluconeogenesis
blood stream to maintain blood glucose levels. Genetic lack of Gluconeogenesis is synthesis of glucose from non-carbohydrate
glucose-6-phosphatase gives rise to von Gierke’s disease, the most sources and is typically active in catabolic states, e.g. post-
common of the glycogen storage diseases. Liver stores about 100 g prandial/starvation, exercise, occurring mainly in the liver
of glycogen, enough to supply the body for only about 12e24 (consistent with its role in maintaining blood glucose levels) and

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 BASIC SCIENCE

Carbohydrate metabolism
glucose

ADP ADP

ATP ATP

glycolysis
NAD + NAD +

NADH NADH

1 2
lactate pyruvate acetaldehyde ethanol
CO2
NAD + NAD +
CO2
3
NADH

acetyl-CoA acetate

Ethanol producing pathways (e.g. yeasts) are shown in colour. Both lactate and ethanol
production are true fermentation reactions. 1: lactate dehydrogenase 2: alcohol
dehydrogenase 3: acetaldehyde dehydrogenase.

Figure 2

with some limited activity in kidney. It allows the body to make pyruvate, which then undergoes gluconeogenesis, regenerating
new glucose when dietary carbohydrate sources are limited, and is glucose for re-export to muscle or erythrocytes: the Cori cycle
regulated by hormones such as glucagon, and by the supply of (Figure 3). In the clinical context, elevated blood lactate is a
substrates. The pathway is not simply a reversal of glycolysis, as common finding in critically ill patients. Hyperlactataemia/lactic
several reactions of glycolysis are irreversible, but many of the acidosis (blood [lactate] >2.5 mM) may be due to increased
steps are shared by both pathways. The substrate for gluconeo- peripheral (extrahepatic) production (e.g. tissue ischaemia/hyp-
genesis is pyruvate, derived from transamination of the amino oxia) but may also be due to decreased central (hepatic) gluco-
acid alanine (derived from proteolysis of body protein) or from neogenesis or liver blood flow, and is an early sign of
re-oxidation of lactate produced from anaerobic metabolism. mesenteric/hepatic ischaemia. This cycle also operates in ma-
Glycerol, derived from lipolysis of triglycerides (triacylglycerols, lignancy. Cancer cells are highly glycolytic, producing lactate
TAG), can also be used for glucose synthesis (and hence although from glucose even in the presence of adequate oxygen; this
fatty acids cannot be converted into glucose, breakdown of stor- aerobic glycolysis is termed the Warburg effect. The lactate is
age lipids does yield a small amount of carbohydrate). Regulation recycled by the ‘host’ liver in an energetically inefficient cycle.
of blood glucose concentration being a major function of liver, Tumours also typically utilize much glutamine; a likely expla-
liver failure is characterized by falling blood glucose levels. nation for these processes is that this provides the tumour with
biosynthetic substrates (including products of the pentose
Lactate and ethanol metabolism phosphate pathway) to support its rapid growth. The cause of the
In tissues with mitochondria and in the presence of oxygen, weight loss and wasting (cachexia) seen in cancer is uncertain
NADH from glycolysis is reoxidized to NADþ by the electron but is probably not solely due to the energetic burden the tumour
transport chain in the inner mitochondrial membrane, with places on the host e a variety of signals, both host and tumour
generation of ATP. In the absence of mitochondria (e.g. eryth- derived (e.g. cytokines such as TNFa (‘cachectin’, oncometabo-
rocytes) or in ischaemic/hypoxic states, NADþ must be regen- lites) are likely involved in the metabolic reprogramming seen in
erated from NADH in the cytosol, by linking pyruvate reduction this condition.
to lactate by lactate dehydrogenase (LDH) to allow glycolysis to Certain organisms (e.g. yeasts) have an alternative strategy to
continue (see Figure 2). Lactate accumulates and glycolysis regenerate NADþ for glycolysis e alcoholic fermentation. Here,
proceeds, providing limited ATP production by anaerobic meta- pyruvate is decarboxylated to acetaldehyde (and carbon dioxide,
bolism: ‘homolactic fermentation’. Tissues lacking oxygen (e.g. the characteristic gaseous product of brewing), which is then
exercising muscle, ischaemic myocardium) or mitochondria reduced to ethanol by alcohol dehydrogenase, linked to the
(erythrocytes) export lactate to the liver where it is re-oxidized to oxidation of NADH, regenerating NADþ (see Figure 2). Ethanol

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 BASIC SCIENCE

The Cori cycle

glucose glucose glucose

gluconeogenesis glycolysis
ATP

pyruvate lactate lactate lactate pyruvate

O2 lack

further oxidation
not possible

liver muscle
Glycolysis yields a small amount of ATP anaerobically, but in the absence of oxygen, pyruvate
cannot be oxidized and must be reduced to lactate. This is transported to liver for regeneration
of glucose. High blood lactate levels can arise from increased peripheral production, but also from
decreased hepatic perfusion or function.

Figure 3

accumulates, and inhibits competing microorganisms. When evolution because lack of NADPH-derived anti-oxidant activity in
ethanol is ingested by humans, its metabolism has multiple ef- erythrocytes inhibits the malaria parasite.
fects on the NADþ:NADH ratio (redox potential). In the liver,
ethanol is oxidized to acetaldehyde by alcohol dehydrogenase, Regulation of carbohydrate metabolism
and acetaldehyde is further oxidized to acetate by aldehyde de- Insulin is the major anabolic signal for carbohydrate metabolism.
hydrogenase, both enzymes generating NADH (and potentially Pancreatic b-cells secrete insulin in response to increased blood
reactive oxygen species). The acetate is converted into acetyl- glucose, which stimulates glucose uptake from the blood, and
CoA, providing an abundant energy source. However, the high anabolic processes such as hepatic glycogenesis and glycolysis,
levels of NADH inhibit oxidation of lactate to pyruvate, limiting resulting in lowered blood glucose. Insulin also inhibits catabolic
the availability of the gluconeogenic precursor and causing a pathways such as glycogenolysis and gluconeogenesis. Sulpho-
mild metabolic lactic acidosis. The result is decreased gluco- nylurea drugs act on ATP-sensitive potassium channels in the
neogenesis and hypoglycaemia. Furthermore, the TCA cycle and pancreatic b-cells to modify the mechanism linking glucose
fatty acid b-oxidation are inhibited, while lipogenesis is increased sensing and insulin secretion by that tissue, causing increased
(increased acetyl-CoA), leading to hepatic lipid accumulation and insulin output. Sympathetic activation and several hormones,
alcoholic fatty liver. including catecholamines, cortisol and growth hormone, stimu-
late hepatic glycogenolysis and gluconeogenesis, with glucose
Pentose phosphate pathway release into the blood, but glucagon is the major catabolic signal,
G6P is also used in the cytosolic pentose phosphate pathway raising blood glucose by stimulating hepatic glucose production
(PPP). The pathway generates NADPH, and the pentose (5- and inhibiting the reciprocal anabolic pathways. Hepatic gluco-
carbon) sugar ribulose-5-phosphate, which is used for synthesis neogenesis is inhibited by the biguanide metformin, decreasing
of nucleotides and aromatic amino acids. NADPH provides en- hepatic glucose production in diabetes.
ergy for certain anabolic reactions, such as lipogenesis, and also
maintains the antioxidant glutathione in its reduced (active) form Lipid metabolism
(GSH). The initiating step of PPP reduces NADPþ to NADPH and
is catalysed by glucose-6-phosphate dehydrogenase (G6PDH). Fatty acids are used for energy production in oxidative tissues.
Deficiency of this enzyme is common in equatorial regions; it is Since they are amphipathic and potentially toxic, their plasma
an X-linked condition and many variants of G6PDH deficiency concentration does not rise to more than w0.5 mM physiologi-
occur. NADPH deficiency secondary to low G6PDH activity re- cally and they are transported bound to albumin (‘free’ fatty
sults in low levels of reduced glutathione and increased oxidative acids are more correctly termed non-esterified fatty acids
damage to erythrocytes, denatured haemoglobin appearing as [NEFA]). Esterification of three fatty acids to glycerol yields the
blister cells and Heinz bodies, presenting as haemolytic anaemia. very hydrophobic TAG e a highly efficient energy storage
Haemolytic crises may be induced by various drugs and chem- molecule. TAG transport in the aqueous plasma requires it to be
icals, including methylene blue, and ingested fava beans carried in the hydrophobic core of TAG-rich lipoproteins
(favism). G6PDH mutations have probably been tolerated in (TGRLP).

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 BASIC SCIENCE

Lipid mobilization CoA (HMG-CoA); HMG-CoA can also be converted to mevalo-

Lipid mobilization occurs during catabolic states such as fasting, nate by HMG-CoA reductase, and eventually to cholesterol (see
starvation and exercise. Adipose tissue stores the greatest Figure 1). HMG-CoA reductase is the rate-limiting step of
amount of TAG (w15 kg), which undergoes lipolysis by the ac- cholesterol synthesis, and is the enzyme inhibited by the statin
tion of lipase enzymes (including hormone sensitive lipase, HSL) class of drugs.
releasing three fatty acids (FA) and one glycerol into the circu-
lation for use elsewhere in the body: glycerol is utilized by the Lipid synthesis and lipoprotein metabolism
liver for gluconeogenesis, the fatty acids are utilized by oxidative Excess acetyl-CoA derived from surplus carbohydrates and
tissues for ATP production. Other tissues store TAG in lipid amino acids is assembled into fatty acids for energy storage
droplets as an intracellular energy resource for their own utili- (lipogenesis) in the cytosol of liver and adipose tissue (see
zation. Recent evidence suggests that excessive tissue lipid Figure 1). The initiating step involves generation of malonyl-CoA
accumulation, for example, in insulin-resistant states such as from acetyl-CoA by acetyl-CoA carboxylase (ACC), and is highly
type 2 diabetes, leads to tissue dysfunction (and further insulin regulated. The malonyl group is the donor for fatty acid syn-
resistance: ‘lipotoxicity’). thetase (FAS), a multicatalytic polypeptide which elongates the
NEFA uptake from the plasma involves both diffusion across growing fatty acid chain by 2 carbons in a repeated cycle using
the cell membrane as well as facilitated uptake via CD36/FAT NADPH for energy. While b-oxidation occurs in mitochondria,
(FA translocase) and FA binding and transport proteins lipogenesis occurs in the cytosol, an example of intracellular
Following uptake, FAs may be re-esterified in the cytosol to compartmentation limiting futile substrate cycling of two
intracellular triglycerides or migrate to the mitochondria for opposing pathways. Three FAs are then esterified to glycerol
oxidation. However, long-chain FAs cannot cross the highly phosphate to form TAG. TAG synthesized in liver must next be
selective inner mitochondrial membrane when bound to their exported to adipose tissue for storage.
carrier, CoA, therefore, the FA is transported across on the TAG must be transported in the plasma within specialized
carnitine shuttle, initiated by carnitine acyl transferase-1 (CAT- carrier particles e lipoproteins. The TAG-rich lipoproteins
1). CAT-1 is inhibited by malonyl-CoA, the first committed in- comprise a phospholipid monolayer shell, embedded proteins
termediate of lipogenesis, a reciprocal mechanism preventing (apolipoproteins, which direct the fate of the particle), a hydro-
simultaneous FA synthesis and breakdown, and a major regu- phobic core of TAG, together with cholesterol (esterified), and
latory mechanism of FA oxidation. fat-soluble vitamins. TGRLPs comprise chylomicrons (CM),
synthesized by the intestine from exogenous dietary fat, and
b-Oxidation very-low-density lipoproteins (VLDL), synthesized by the liver
Fatty acids within the mitochondria now undergo b-oxidation. from endogenous lipids. CM and VLDL deliver TAG to FA-
The b-carbon of the FA chain is attacked and a 2-carbon segment utilizing tissues that express the enzyme lipoprotein lipase
of the FA chain is released as acetyl-CoA. This oxidative cycle is (LPL), which is tethered to the luminal surface of the endothe-
repeated until the entire FA chain has been broken down to lium. In type I hyperlipoproteinaemia (chylomicronaemia) syn-
multiple acetyl-CoA, NADH and FADH2. The acetyl-CoA un- drome, an autosomal recessive mutation of LPL, plasma TGRLP-
dergoes further oxidation in the TCA cycle; all the NADH and TAG cannot be cleared and very high (>50 mM) plasma TAG
FADH2 generated are then oxidized by the electron transport levels result. (More rarely, a mutation in the LPL-activating
chain, yielding large amounts of ATP (see Figure 1). Many forms apoprotein apo-CII causes a similar clinical picture.)
of mitochondrial disease based on enzyme mutations are now Following LPL action the lipoprotein shrinks, resulting in a
recognized, often presenting with muscle weakness but demon- smaller, denser, TAG-depleted particle named a ‘remnant parti-
strating a wide variety of phenotypes. Medium-chain acyl-coen- cle’. The chylomicron remnant is recycled in the liver; the VLDL
zyme A dehydrogenase (MCAD) deficiency impairs the remnant particle is termed low-density lipoprotein (LDL), and
b-oxidation of fatty acids within the mitochondria, limiting their continues in the circulation to deliver its remaining core lipid e
use as a fuel in oxidative tissues and increasing the dependence cholesterol ester e to peripheral tissue through a lipoprotein
on glucose metabolism for ATP production. receptor-mediated uptake mechanism, resulting in the entire LDL
particle being endocytosed into the target cell for cholesterol
Ketone bodies release. This mechanism is termed ‘forward cholesterol trans-
In the liver, acetyl-CoA derived from b-oxidation can also be port’. Excess cholesterol is transported back from peripheral
used for ketone body synthesis (ketogenesis). The ketone tissues to the liver for excretion by the ‘reverse cholesterol
bodies, acetoacetate and b-hydroxybutyrate, are water soluble transport’ pathway: nascent high-density lipoprotein (HDL)
transportable forms of acetyl-CoA, which can be used by the particles in the plasma assimilate cholesterol from extrahepatic
brain and other oxidative tissues as glucose-sparing fuels in tissues, then the cholesterol-enriched HDL particle is removed by
catabolic conditions such as starvation. Ketogenesis occurs the liver and the cholesterol excreted in the bile. Defects in li-
exclusively in the liver; however, liver lacks the pathway for poprotein receptor expression, for example lack of functional
ketone body utilization (ketolysis), preventing futile substrate LDL receptor in familial hypercholesterolaemia (Fredrickson type
cycling. Acetoacetate undergoes spontaneous decarboxylation II hyperlipidaemia), are characterized by an inability to remove
to acetone, which probably has no physiological function in LDL cholesterol from the circulation, resulting in very high
humans but is volatile and excreted in the breath, with a plasma LDL-cholesterol levels (>10 mM) and accelerated
characteristic sweet-smelling odour present in diabetic ketoaci- atherosclerosis. By contrast, high levels of HDL are associated
dosis. An intermediate of ketogenesis is hydroxymethylglutaryl- with decreased risk of atherosclerosis.

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 BASIC SCIENCE

Regulation of lipid metabolism regenerating a-ketoglutarate and producing NH3. The ammonia
The anabolic state is signalled by insulin: hepatic lipogenesis, is then detoxified to urea in the urea cycle, and carbon skeletons
TAG and cholesterol synthesis are stimulated, while ketogenesis undergo intermediary metabolism (see below; Figure 5).
is inhibited. In adipose tissue, insulin stimulates LPL, enhancing The urea cycle occurs in the liver. Urea (CO.(NH2)2) contains
plasma TAG uptake from TGRLPs, and suppresses TAG lipolysis, two nitrogen atoms: one derives from NH3 via oxidative deami-
thereby lowering plasma NEFA concentrations. Conversely, nation of glutamate, the other from aspartate via transamination
several catabolic ‘counter-regulatory’ hormones and signals by AST. Each of the six enzymes of the urea cycle may be func-
stimulate lipid mobilization and breakdown e catecholamines, tionally mutated, impairing ammonia disposal. Ornithine trans-
increased sympathetic activity, and adrenocorticotrophic hor- carbamylase (OTC) is a mitochondrial urea cycle enzyme which
mone (ACTH) stimulate adipose lipolysis, increasing plasma synthesizes citrulline from ornithine and carbamoyl phosphate
NEFA levels. (the latter formed from ammonia and bicarbonate). OTC defi-
ciency is the most common disorder of the urea cycle and is
Amino acid metabolism characterized by high ammonia concentrations, causing ataxia,
lethargy and death, reflecting the extreme neurotoxicity of NH3.
Typical dietary protein intake is w100 g/day, while the w10 kg The mechanism of this severe neurotoxicity is not fully under-
of body protein is turned over at w300 g/day (w3%). Dietary stood, but excess free ammonia in the CNS may cause reversal of
proteins are absorbed as amino acids and small peptides into the glutamate dehydrogenase, with glutamate formation e this de-
portal circulation, with enterocytes and hepatocytes oxidizing pletes a-ketoglutarate, a key TCA cycle intermediate and hence
some amino acids as their main substrate. Amino acids are also depletes ATP. Since glutamate is an excitatory neurotransmitter,
derived from proteolysis of endogenous proteins, and some this may also account for the observed effects on neural function.
(‘non-essential’) can be synthesized from intermediary metabo-
lites or from other amino acids. In contrast, ‘essential’ amino Metabolism of carbon skeleton
acids cannot be synthesized by humans and must be obtained Following deamination, the remaining carbon skeleton enters the
from the diet. Unlike carbohydrates and lipids, amino acids common metabolic pool (see Figure 1). All amino acids ulti-
contain nitrogen in the form of an amino group and this must be mately yield just seven products of intermediary metabolism:
removed (deamination) before the remaining carbon skeleton (2- pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, oxaloacetate,
oxoacid) can undergo further metabolism (Figure 4). Deamina- acetyl-CoA and acetoacetyl-CoA. The first five of these represent
tion of amino acids produces ammonia (NH3), which is highly 3 carbons, hence amino acids producing these metabolites can
toxic and must be either excreted directly into the urine by the be used for glucose synthesis (by gluconeogenesis: ‘glucogenic’):
kidney, or converted into relatively non-toxic urea by the urea it is this property that confers on proteins the ability to act as a
(ornithine) cycle in the liver. carbohydrate reserve. The acetyl-CoA and acetoacetyl-CoA,
however, yield two (or two-equivalent) carbons, and amino
Nitrogen disposal acids which produce them cannot be used for gluconeogenesis e
Deamination of amino acids is achieved by two types of reaction they can be directly oxidized in the TCA cycle, undergo lipo-
acting together. In transamination, the amino group from one genesis or be used to synthesize ketone bodies (‘ketogenic’).
amino acid is transferred to another carbon skeleton (an oxoa- Inborn errors of metabolism of several amino acids exist.
cid), forming its corresponding amino acid (i.e. amino acid-1 þ In alkaptonuria, the gene for the enzyme homogentisate 1,2-
oxoacid-2 4 oxoacid-1 þ amino acid-2). For most amino acids dioxygenase is functionally mutated. This enzyme is required
undergoing transamination the amino acceptor is a-ketoglutarate for the metabolism of the carbon skeletons of phenylalanine and
(a TCA cycle intermediate), producing the carbon skeleton of the tyrosine to acetoacetyl-CoA. Lack of enzyme activity results in
donor amino acid and glutamate. Hence a-ketoglutarate ‘funnels’ accumulation of the intermediate homogentisic acid; its metab-
the various amino acids into glutamate via transamination olite alkapton gives the urine a black appearance when exposed
(Figure 5). Alanine aminotransferase (transaminase; ALT) to air. The inborn error of metabolism phenylketonuria is also
transfers the amino group of alanine to a-ketoglutarate, forming due to a mutation in this same pathway, but the striking differ-
pyruvate and glutamate. Alanine is a key transport amino acid in ence in disease severity lies in the different metabolites that
the blood, safely conveying nitrogen from peripheral tissues such accumulate when the pathway is blocked further upstream.
as muscle to the liver, hence this enzyme is important for inter-
tissue amino acid flux. Aspartate aminotransferase (trans- Inter-tissue amino acids flux
aminase; AST) transfers the amino group of aspartate to a- Liver is the site of both ureagenesis (amino-N metabolism) and
ketoglutarate, forming oxaloacetate and glutamate but this gluconeogenesis (carbon skeleton metabolism), and removes
enzyme usually works in the reverse direction, converting most dietary amino acids from the portal circulation in the
glutamate (from funnelled amino acids, above) into aspartate, anabolic state, together with amino acids derived from proteol-
which is required to donate a second N-atom to the urea cycle. ysis in extrahepatic tissues in catabolism. The muscle exports a
Since ALT and AST are both intracellular enzymes and wide- large amount of its amino acids from proteolysis as alanine,
spread, necrosis of many tissues releases them to plasma, but derived from the transamination of multiple amino acids
they are commonly used to diagnose hepatocellular damage. The donating their amino group to glycolytically derived pyruvate.
second type of deamination reaction is oxidative deamination: The alanine is transported to the liver, where it is transaminated
following transamination in liver, the glutamate undergoes direct to reform pyruvate, which undergoes gluconeogenesis to glucose
oxidative deamination by glutamate dehydrogenase, (Figure 5). The glucose is re-exported back to muscle (the

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 BASIC SCIENCE

Amino acid metabolism

amino acid

deamination

NH3 carbon skeleton

urea
cycle

TCA intermediates acetyl-CoA

(glucogenic) acetoacetyl-CoA
(ketogenic)
urea

glucose ketone bodies

fatty acids

CO2 + H2O + ATP

The metabolic fate of the carbon skeleton depends on where it enters the pathway of
intermediary metabolism. TCA, tricarboxylic acid.

Figure 4

glucoseealanine cycle). Amino acids are also exported from The three branched-chain amino acids (BCAA) (leucine,
muscle as glutamine, which contains two amino groups and is a isoleucine and valine) make up approximately one-third of all
major transporter of amino groups. The kidney utilizes gluta- amino acids in the body. Dietary BCAAs are not removed from
mine, removing the side chain amino group with glutaminase, the portal circulation by the liver, appearing in high concentra-
reforming glutamate and free ammonia. Ammonia is excreted tion in the splanchnic blood, where they may also have a role as
directly in the urine as a urinary buffer (achieving buffering nutrient signals. They are metabolized in extrahepatic tissue,
capacity in a waste product without losing substrate). especially muscle, where they are major sources of nitrogen to

oxidative
transamination transamination
deamination

CO2

alanine -KG NH3 aspartate -ketoglutarate

glutamate aspartate
alanine urea cycle
dehydrogenase aminotransferase
aminotransferase

pyruvate glutamate oxaloacetate glutamate

(carbon skeleton)

urea
intermediary
metabolism

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ‘funnel’ amino acids (e.g. from
muscle protein) by transamination into glutamate for deamination and urea formation.

Figure 5

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 BASIC SCIENCE

maintain pools of glutamine, glutamate and alanine. All three are as signalling starvation and the above catabolic state results.
transaminated by a single branched-chain aminotransferase, and However, the patient is not starving (indeed is still eating) so
the resulting branched-chain 2-oxoacids (a-ketoacids) undergo dietary glucose also enters the circulation, resulting in extreme
oxidative decarboxylation by a branched chain a-ketoacid de- hyperglycaemia. The excess plasma glucose appears in urine
hydrogenase. Absence of this enzyme is responsible for maple (glycosuria) as the renal tubular reabsorption maximum is
syrup urine disease, whereby BCAAs are transaminated to their exceeded, and this carries water with it osmotically, resulting in
corresponding branched chain a-ketoacids, but absence of the polyuria (osmotic diuresis), dehydration, thirst and polydipsia.
dehydrogenase means these intermediates accumulate, appear- However, lipid metabolism is also involved as adipose tissue
ing in the urine and giving it its characteristic maple syrup odour. responds to low insulin by increasing TAG lipolysis, with
excessive NEFA release into the circulation. The NEFA is utilized
Regulation of amino acid metabolism by muscle, further decreasing glucose utilization, and by liver for
Insulin is the main anabolic signal for protein metabolism, ketogenesis. The ketone bodies also inhibit glucose utilization,
stimulating protein synthesis and inhibiting proteolysis. Net spill over into the urine (ketonuria), and being acidic cause a
protein synthesis is also stimulated by muscle training, growth metabolic (keto-)acidosis. This is compensated by increased
factors, growth hormone and anabolic steroids. Protein break- ventilation e Kussmaul breathing e and the volatile 3-carbon
down is stimulated by cortisol and thyroid hormones. Amino acetone produced from acetoacetate may be noticed by its
acids act as nutrient signals in pancreatic b-cells, modulating characteristic smell on the breath.
insulin secretion.
Sepsis, trauma
Diabetes
Besides diabetes and tumour growth, the catabolic state can also
Blood glucose and certain amino acids e arginine, leucine e are be triggered by an excessive inflammatory reaction, characterized
sensed by pancreatic b-cells: high levels indicate nutrient reple- by the appearance of pro-inflammatory cytokines, such as TNFa,
tion, and this anabolic state is signalled to the rest of the body by IL-1b and IL-6 in the blood stream, where their normally local
insulin release. Hence, the pancreas detects glucose while the paracrine effects are superseded by more general endocrine effects
rest of the body then detects insulin. Insulin is the sole anabolic on metabolism. In sepsis this is a reflection of a generalized and
hormone, responsible for disposition of carbohydrates, lipids and excessive activation of the immune system secondary to pathogen
amino acids; its actions are opposed by multiple catabolic sig- invasion and host immune cell activation, resulting in an unreg-
nals. Consequently, insulin deficiency has severe and pleiotropic ulated increase in mobilization and availability of all (carbohy-
metabolic consequences. Inhibition of catabolic (substrate drate, lipid, amino acid) substrate. In trauma, a comparable
mobilizing) pathways by insulin is as critical as stimulating picture occurs. Cuthbertson described the phases of response to
anabolic (substrate storage) pathways. In low-insulin states, less trauma as the ‘ebb phase’ (now usually termed shock: hours), the
inhibition of catabolism, together with lack of anabolic stimula- ‘flow phase’ (now generally referred to as the catabolic flow
tion, causes default to catabolism and net substrate mobilization. phase: days) and ‘recovery’ (anabolic flow phase: weeks), and we
In starvation, falling blood glucose levels are detected by the understand this as being the result of generalized neurohumoral
pancreas, which responds with decreased insulin secretion. activation, stimulating catabolic pathways and inhibiting sub-
Peripheral tissues interpret falling insulin as indicating whole- strate storage. Sepsis, trauma and burns are therefore associated
body nutrient depletion and respond by becoming catabolic, with a generalized, potentially unregulated inflammation e the
decreasing substrate uptake and mobilizing energy reserves. The systemic inflammatory response syndrome (SIRS). Failure of the
liver responds to low insulin as indicating hypoglycaemia, and body to adequately counter the primary pathological insult and to
increases glucose production by glycogenolysis and gluconeo- regulate its response to it leads to multiorgan failure and/or crit-
genesis. The gluconeogenic substrate is alanine, derived from ical illness myopathy/polyneuropathy, with substrate depletion
increased proteolysis and muscle wasting. Hence carbohydrate and wastage. A
(glycogen) and amino acid (protein) reserves are consumed to
increase substrate provision. Because insulin remains low, the
catabolic state continues and substrate mobilization prevails. In FURTHER READING
addition to increased hepatic glucose production, peripheral Frayn KN, Evans RD. Human metabolism: a Regulatory perspective.
glucose utilization via glucose uptake, glycolysis and glycogen- 4th ed. Oxford: Wiley-Blackwell, 2019.
esis is decreased, in an attempt to spare glucose. Adipose tissue Hue L, Taegtmeyer H. The randle cycle revisited: a new head for an old
responds to decreased insulin by increasing lipolysis, leading to hat. Am J Physiol Endocrinol Metab 2009; 297: E578e91.
fatty acid and glycerol release, providing substrate for oxidation McKnight SL. On getting there from here. Science 2010; 330: 1338e9.
(FA) as well as limited gluconeogenesis (glycerol). Increased Murphy M, Srivastava R, Deans K. Clinical biochemistry. 6th ed.
delivery of NEFA to liver leads to ketogenesis and ketonaemia, Elsevier, 2018.
ketone bodies being an important glucose-sparing fuel for Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-
brain, which cannot utilize FAs directly. In type 1 diabetes acid cycle. Its role in insulin sensitivity and the metabolic distur-
mellitus, pancreatic b-cells are destroyed, so there is no longer bances of diabetes mellitus. Lancet 1963; 1: 785e9.
any effective glucose sensing mechanism, nor means to signal Salway JG. Metabolism at a glance. 6th ed. Oxford: Wiley-Blackwell,
the anabolic state. The lack of insulin is interpreted by the body 2016.

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