BASIC SCIENCE

Lipid metabolism of lipids, relates to their structure and function in cell membranes
and role as a major energy source. In this respect, it is important to
distinguish between structural lipids within cell membranes and
Bruce A Griffin
stored lipids in tissues.

Structural lipids
Abstract Lipids in the human body exist as structural lipids in cell mem-
Lipids are body fats that are either synthesized within cells (endogenous branes and as stored lipids in body fat or adipose tissue. The lipids
lipids) or derived from dietary fat (exogenous lipids). They are typically char- transported in serum lipoproteins could be viewed, at least in a
acterized by their insolubility in water, and have a diverse range of biological physical sense, as a mobile intermediate of membrane and storage
functions in cell membranes as phospholipids, and as a major source of lipids, which provide a vital transport link between the two. The
stored energy in adipose tissue as triacylglycerols (TAGs). Serum lipids, composition and metabolic fate of membrane and stored lipids are
including TAGs, phospholipids, cholesterol and their component fatty quite distinct, although many of the fatty acids are the same in both.
acids, are transported between sites of synthesis in the liver and intestine The main components of both membrane and storage lipids are the
to peripheral tissues, for utilization and storage in macromolecular com- long-chain (16e24 carbon) saturated, mono-unsaturated fatty
plexes of lipid and protein called lipoproteins. The physiology of circulating acids and polyunsaturated fatty acids (PUFAs), although several of
serum lipoproteins is described in terms of the transport of exogenous and the major long-chain fatty acids (LCFAs) in the body are common to
endogenous chylomicrons and very low-density lipoproteins, respectively. both membrane and storage lipids, such as palmitate, stearate,
These TAG-rich lipoproteins are remodelled under the action of lipoprotein oleate and linoleate. Biological membranes surrounding cells and
lipase and lipid transfer proteins into smaller chylomicron remnants and subcellular organelles exist primarily as lipid bilayers. This struc-
low-density lipoproteins (LDLs). These cholesterol-rich lipoproteins deliver tural arrangement is made possible by the dual polarity of phos-
cholesterol back to the liver and peripheral tissues via specific membrane re- pholipids, in other words, the presence of hydrophilic and
ceptors, but can promote atherosclerosis by depositing themselves and their hydrophobic domains that spontaneously associate with water and
cholesterol in artery walls. In contrast to this forward transport of cholesterol lipid environments, respectively. This ‘amphipathicity’ makes
into tissues, reverse cholesterol transport describes the pathway which phospholipids ideal building blocks for the construction of bi-layers
leads cholesterol away from peripheral tissues and back to the liver. This in cell membranes, and for the purpose of packaging hydrophobic
function is performed by high-density lipoproteins (HDLs), and confers pro- lipids (cholesterol esters and triacylglycerols (TAGs)) for transport
tection against atherosclerosis. The metabolism of TAG-rich lipoproteins, in the circulation in the form of serum lipoproteins. The lipids in
and the inter-relationship between these processes and HDL, particularly both the inner and outer surfaces of cell membranes are composed
in the post-prandial period, determines the extent to which LDL and HDL mainly of phospholipids and free cholesterol, which interface with
can promote and prevent atherosclerosis, respectively. functional proteins that act as receptors, transporters, enzymes, co-
enzymes and ion channels. PUFAs produce a relative increase in
Keywords Cholesterol; high-density lipoprotein; lipoproteins; low-den- membrane ‘fluidity’ in comparison to free cholesterol and saturated
sity lipoprotein; low-density lipoprotein post-prandial lipaemia; low- fatty acids, which exert a rigidifying effect. Thus, the relative pro-
density lipoprotein receptor; phospholipids; triacylglycerol portion of these different fatty acids is of physiological relevance
through its influence on the movement, conformation and function
of membrane-bound proteins.
Much of our knowledge of the relationship between lipid meta- Membrane phospholipids express a diverse range of fatty acid
bolism, health and cardiovascular disease comes from our un- profiles depending on their tissue and sub-cellular location. They
derstanding of the physiology of plasma lipoproteins. For this contain a high proportion of long-chain PUFAs, such as arach-
reason, the following review explores lipid metabolism, primar- idonate, that can be released by a phospholipase A2, not to generate
ily from the perspective of the extracellular transport of lipids in energy per se, but as synthetic precursors of compounds called ei-
plasma lipoproteins. Less emphasis has been placed on more cosanoids. These hormone-like compounds exert powerful meta-
basic, but equally important, aspects of lipid metabolism, bolic effects on neighbouring tissues (paracrine function). They are
including the biochemistry of individual fatty acids. synthesized from long-chain PUFAs via the actions of cyclo-
oxygenases and lipoxygenase, producing a range of cyclic proste-
Lipids: structure and function noids (prostacyclin, prostaglandins, thromboxanes) and leukotri-
Lipids may be distinguished from proteins and carbohydrates by enes, respectively. These compounds influence a range of
their relative insolubility in water, and have been grouped histori- physiological processes, and modulate inflammation and immune
cally into simple, compound (complex), derived and miscellaneous reactions. The composition of membrane fatty acids and their
lipids. This definition is now a little outdated, and of limited value in respective eicosanoids, can be modified by altering the composition
understanding the dynamics of lipid metabolism. A more contex- of dietary fats. In this way, diet has the potential to impact on health
tually relevant definition, which reflects the diverse metabolic effects and diseases with an inflammatory or immune basis, by changing
the spectrum of eicosanoids.1

Storage lipids
Bruce A Griffin BSc PhD RNutr is a Professor of Nutritional Metabolism with
Expertise in Lipid Biochemistry at the Faculty of Health and Medical TAG, a triester of glycerol, is the main energy storage form of
Sciences, University of Surrey, UK. Conflicts of interest: none declared. lipids and the principal component of adipose tissue. Composing

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 BASIC SCIENCE

approximately 80% of the weight of this tissue, it represents the The absorption of LCFA and 2-MAG from the mixed micelle
main body pool of palmitate, stearate, oleate and linoleate. Fatty occurs by facilitated diffusion, assisted by the action of fatty acid-
acids destined for oxidation are also present in TAGs in binding proteins in the cell membrane which increase membrane
measurable but lesser quantities in all tissues that can oxidize permeation. An additional process which drives the diffusion
LCFAs, including muscle and heart. TAGs are synthesized by the gradient is the rapid re-esterification of LCFA into 2-MAG, and 2-
intestine and liver, where they are subsequently incorporated MAG into TAGs within the enterocyte by the enzyme acyl-CoA:
into lipoproteins for transport from their sites of synthesis to cholesterol acyltransferase (ACAT). The absorption of dietary
tissues in which they are oxidized or stored. Adipose tissue exists TAG in the small intestine is extremely efficient, with about 90%
in two forms that are distinct with respect to their location and being absorbed, whereas only about 40% of dietary cholesterol is
metabolic behaviour, namely subcutaneous and visceral adipose absorbed directly. Liberated fatty acids of short and medium
tissue. Visceral adipose tissue is deeper and more central in its chain length (<12 carbons) are absorbed directly into the portal
location, and in closer proximity to internal organs including the circulation with free glycerol, and transported with albumin to
liver. These two types of fat tissue differ in their response to the liver where they are rapidly oxidized. In contrast, longer-
neuroendocrine and metabolic stimuli, which can accelerate or chain fatty acids (12 carbons) associate with bile acids, and
suppress the release or accumulation of fatty acids. A third form are absorbed into the enterocyte for further processing and
of stored fat that is deposited within vital organs, such as the packaging into serum lipoproteins.
liver and pancreas, is known as ectopic fat. The accumulation of
both visceral and ectopic fat has been implicated as a causal Entero-hepatic circulation
factor in the development of insulin resistance and related co-
The absorption of fat in the small intestine is highly dependent
morbidities associated with central obesity, metabolic syn-
on the availability of bile acids from biliary secretions, which
drome and type 2 diabetes.2
also contain free cholesterol (1 g/day), after which the bile acids
(>95%) and biliary cholesterol are eventually salvaged by an
Fat digestion, absorption and post-prandial lipid transport energy-dependent re-absorption in the terminal ileum (entero-
The average daily intake of fat in a Western diet ranges from 50 hepatic circulation). The extent of this re-absorption is tightly
to 100 g, and provides between 35 and 40% of total energy. It controlled by a feedback mechanism that is sensitive to levels of
consists mainly of TAGs, which form the principal component of free cholesterol in the liver, such that the re-absorption of bile
visible oils and fats, phospholipids and milligrammes of choles- acids suppresses the activity of 7-a-hydroxylase, slowing the
terol. The digestion of dietary fat involves mechanical emulsifi- further production of bile acids. This pathway has been exploited
cation in the stomach, lipolytic breakdown by lipases and extensively by the use of drugs and soluble dietary fibres that can
solubilization with bile salts in the duodenum, and, finally, ab- bind and prevent the re-absorption of bile acids. This, in turn
sorption into the epithelial cells or enterocytes which line the promotes bile acid production and depletion of hepatic choles-
luminal surface of the upper small intestine. terol, an effect that results in a lowering of serum low-density
Lipolysis describes the enzyme-catalysed breakdown of lipoprotein (LDL) cholesterol via activation of the LDL receptor
complex lipids, which results in the release of fatty acids from pathway (see below).
TAGs, phospholipids and cholesterol esters. It involves the hy-
Re-esterification of triacylglycerol in the enterocyte
drolytic cleavage of bonds between a fatty acid and the glycerol
backbone of TAG and phospholipids, and cholesterol esters, and Once LCFAs have entered the enterocyte they are activated by
occurs not only in the digestive tract, but also in circulating and acyl-CoA and are re-esterified with glycerol back into TAG and
intracellular lipids. The lipolysis of emulsified fat entering the phospholipids by either the 2-MAG and/or glycerol-3-phosphate
duodenum is catalysed by pancreatic lipase, an extra-cellular pathways. The difference between these two pathways lies in: (1)
enzyme which acts chiefly on dietary fat (TAG), in concert the substrates of activation, the former using 2-MAG and the
with the actions of phospholipase and cholesterol ester hydro- latter a-glycero-3-phosphate; (2) their location within different
lase. Pancreatic lipase hydrolyses fatty acids in a sequential cellular organelles, 2-MAG and glycerol-3-phosphate residing in
fashion with the initial removal of a fatty acid from position 1 the smooth and rough endoplasmic reticulum (ER) respectively;
and then position 3 from the glycerol backbone, generating a 2,3- (3) the periods during which they are most active, the 2-MAG
diacylglycerol, followed by a 2-mono-acylglycerol (2-MAG). pathway being quantitatively more important in the enterocyte
Fats are solubilized in the duodenum by interfacing with phos- in the gut in the post-prandial period, whilst glycerol-3-
pholipids and the primary bile acids, cholic and chenodeoxycholic phosphate is more active in the post-absorptive phase in liver,
acids, which are produced from cholesterol in the liver under the muscle and adipose tissues. Up to 90% of these molecules are
action of the rate-limiting enzyme 7-a-hydroxylase. These bile salts rapidly acylated back to 1,2-diacylglycerol, and finally TAG, via
act as detergents, solubilizing lipids to form mixed micelles, the sequential actions of three enzymes: CoA ligase, mono-
spherical associations of amphipathic molecules that encapsulate a glycerol acyltransferase and diacylglycerol acyltransferase. In a
hydrophobic core of more insoluble longer chain fatty acids (LCFA) similar fashion, lysophosphatidylcholine, produced by the action
and 2-MAG and lipid-soluble vitamins (tocopherols and caroten- of pancreatic phospholipase on dietary phospholipids, is absor-
oids). The formation of mixed micelles increases the solubility of fat bed by the enterocyte and re-esterified back to phosphatidyl-
by between 100- and 1000-fold, and creates an acidic micro- choline in the enterocyte by direct acylation. The bulk of free
environment for the lipid core, which facilitates the dissociation cholesterol absorbed from the intestinal lumen is also re-
and diffusion of LCFA and 2-MAG into the enterocyte in the gut wall. esterified in the enterocyte by the enzyme ACAT.

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 BASIC SCIENCE

Plasma lipoproteins: structure and function from peripheral tissues back to the liver. This direction-based
terminology can be misleading, since all pathways include
Lipoproteins are spherical, macromolecular complexes of hy-
some degree of passage back to the liver.
drophobic lipids (TAG and cholesterol esters) surrounded by a
hydrophilic coat of phospholipids, free cholesterol and special-
Exogenous lipid transport
ized amphipathic proteins called apoproteins (Figure 1). Their
principal function is to transport exogenous lipids (re-synthe- After the absorption of dietary fat in the small intestine, newly re-
sized in the gut from dietary fats), and endogenous lipids (syn- esterified TAG and cholesterol esters associate with specific
thesized in the liver) from these sites of synthesis to peripheral apoproteins and phospholipids in the enterocyte to form the
sites of utilization (e.g. oxidation in muscle, incorporation in largest and most TAG-rich lipoproteins known as chylomicrons
membranes or as precursors of biologically active metabolites) (CMs). The enterocyte can synthesize three apoproteins: apo A-I,
and storage (e.g. adipose tissue). Lipoproteins have been defined apo IV and apo B (B-48). The latter is expressed in two isoforms:
traditionally by density, as determined by their flotation in the the arbitrarily named apo B-100 which is synthesized in the liver,
ultracentrifuge, a property governed chiefly by their relative and a shorter relative apo B-48 which is produced by the enter-
proportion of lipid to protein. Because lipids occupy a greater ocyte and is approximately 48% of the size of apo B-100. Apo B-
molecular volume than proteins, and are lighter and less dense, 48 is produced in the rough ER and transferred to the smooth ER
lipoprotein becomes progressively denser and smaller in size as where it combines with a lipid droplet; it then migrates to the
the ratio of lipid to protein decreases. This compositional feature Golgi apparatus where it combines with other apoproteins (apo
relates directly to the transport function and metabolic inter- A-I, IV). These are glycosylated before CMs eventually leave the
relationships between lipoprotein classes in blood. It can also enterocyte by exocytosis through the basement membrane,
be exploited to separate lipoproteins in the laboratory, because across the intracellular space between the enterocyte and the
lipoproteins of different density float at different rates when lacteal, and are finally discharged into the lymph.
subjected to centrifugal force. Lipoproteins may also be sepa-
rated on the basis of their net charge, particle size and immu- Post-prandial lipid metabolism
nological characteristics conferred by their principal apoproteins
The turbidity of serum following the ingestion of dietary fat
(Table 1). The principal lipoproteins (very low-density lipopro-
marks the arrival of CMs in the blood. The turbidity is produced
tein (VLDL), LDL and high-density lipoprotein (HDL)) all express
by the CMs themselves, which are of a sufficiently large size to
structural heterogeneity, and exist in serum as structurally
physically scatter light and create the turbid, milky appearance of
discrete subclasses with distinct metabolic properties, and the
post-prandial serum. The size and composition of CMs produced
potential to either promote or protect against atherosclerosis.
after a fatty meal is determined by the fat content of the meal.
Hence, the fatty acids in CMeTAG reflect the fat composition of
Lipoprotein transport
the meal. Each CM particle carries a single molecule of apo B-48
Lipoprotein transport (Figure 2) can be described in terms of the which, unlike apos A-I and IV, remains with the CM throughout
production, transport and removal of cholesterol and TAG from its life in the circulation. As the amount of fat arriving in the
the circulation, although to separate the metabolism of these enterocyte increases, the cell packages more TAG into each CM
lipids is artificial as both are transported in lipoproteins. Lipid particle, increasing its size, rather than increasing the number of
transport may also be described in terms of the ‘forward’ and CMs. Lipids in CMs that are enriched with PUFAs are larger than
‘reverse’ transport of cholesterol. In this case, ‘forward’ transport those with saturated fat, as the former occupies more space when
indicates the arrival of cholesterol in the blood from the gut packaged into a lipoprotein. This has implications for the meta-
(exogenous) and liver (endogenous) and carriage back to the bolic fate of these lipoproteins in the circulation, as TAG in larger
liver, whereas ‘reverse’ transport (HDL pathway) is the move- CMs is hydrolysed preferentially by lipoprotein lipase (LPL).
ment of cholesterol in the opposite direction, that is the efflux The onset, duration and magnitude of post-prandial lipaemia
can be monitored in the laboratory after a standard fat-containing
meal by making serial measurements of plasma TAG or, more
specifically, TAG associated with TAG-rich lipoproteins or serum
General structure of plasma lipoproteins apo B-48, at 8 or 9 hours after a meal. Post-prandial lipaemia
normally peaks between 3 and 4 hours after meal, and subsides
to baseline concentration after between 5 and 6 hours. The hy-
Triacylglycerol
drolysis and absorption of dietary fat, re-esterification of TAG
Cholesteryl esters
and lipoprotein assembly in the enterocyte takes approximately
Phospholipid
15 minutes. This means that the almost immediate rise in serum
Free (unesterified) cholesterol
TAG after the ingestion of fat must be explained by the excursion
Apoproteins
of stored lipid from the enterocyte from the previous meal. This
stored TAG is shunted into the circulation by the incoming fat
load, which follows within 30 minutes and can peak within
1 hour after ingestion.
The TAG in circulating CMs is lipolysed by a rate-limiting lipase
known as lipoprotein lipase. LPL is an extra-cellular enzyme,
Figure 1 tethered to the endothelial lining of blood vessels in peripheral

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 BASIC SCIENCE

Physical and compositional properties of the principal plasma lipoproteins

Lipoprotein Density (kg/litre) Size (nm) Mass (3106 Da) Molecules/particle Principal apoproteins
Cholesterol TAG

CM <0.95 80e1200 500 60,000 50,000 B-48, A-1, C-II, E

VLDL 0.95e1.006 30e52 6e50 10,000 24,000 B-100, C-II, E
IDL 1.006e1.019 24e30 2.2e6.0 e e B-100, C-II, E
LDL 1.019e1.063 18e24 1.8e2.2 2000 300 B-100, C-II
HDL 1.063e1.210 8e15 0.2e1.8 e e A-I, A-II, E

CM, chylomicron; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TAG, triacylglycerol; VLDL, very low-density lipo-
protein.

Table 1

tissues, most notably muscle and adipose tissue, by proteoglycan smaller VLDL particles at all times. Finally, during their passage
fibres, and as such is known as an endothelial lipase. Both the through the liver, CMRs bind to specific receptors on the surface of
exogenous and endogenous (VLDL) pathways compete for the hepatocytes (LDL receptor-related protein (LRP) or remnant re-
action of LPL by what is known as the common saturable lipolytic ceptor). The LRP receptor recognizes apo E on the surface of CMRs,
pathway. This consists of a delipidation cascade in which the TAG- an apoprotein that is also acquired by CMs from HDL at an early
rich lipoproteins (CMs and VLDL), after receiving apo C-II from stage. These receptors are maintained at a very high level of activity
HDL, an essential co-factor for the activation of LPL, are progres- and, in contrast to the LDL receptor pathway, are not down-
sively depleted of their TAG in a stepwise fashion by LPL to become regulated through a feedback mechanism (see LDL receptor).
smaller, cholesterol-rich CM remnants (CMRs), which are removed
by specific, high-affinity receptors found chiefly in the liver. Is coronary atherosclerosis a post-prandial phenomenon?
Several molecules of LPL may bind to a single CM or VLDL particle,
Patients with or at high risk of developing coronary heart disease
although LPL shows greater affinity for CM in preference to VLDL.
(CHD) have been shown to express an impaired capacity to
These events generate competition between TAG-rich lipoproteins,
remove TAG-rich lipoproteins, including CMRs, from the circu-
and provide a mechanism to explain how the long-term metabolic
lation after a meal.3 This effect, which has been linked to a
status of the liver and VLDL production, can influence the short-
suppression of LPL activity and/or the overproduction of VLDL,
term clearance of TAG in the post-prandial period. VLDLs are
increases both the duration and magnitude of post-prandial
similar in lipid composition to CMs, but are considerably smaller in
lipaemia, causing an apparent intolerance to dietary fat. This
size. Although CMs carry up to 80% of the TAG during the post-
impaired clearance of TAG in the postprandial phase results in
prandial period they are significantly outnumbered by the
both direct and indirect effects on serum lipoproteins which may
accelerate atherosclerosis. Firstly, it increases the serum resi-
dence time and thus interaction of cholesterol-enriched CMRs
Lipoprotein transport pathways with the arterial wall. Secondly, it stimulates the remodelling of
LDL and HDL into smaller and denser particles and the formation
of an atherogenic lipoprotein phenotype (see below). While
Liver small, dense LDL has increased potential to infiltrate the artery
wall and promote atherosclerosis, small, dense HDL is rapidly
B1 po
00
A

VLDL LDL LDL-R broken down and leaves the circulation, which effectively
removes the cardio-protective function of this lipoprotein. The
1
-1

1
,C

CETP CETP
oA
oE

Ap
Ap

LCAT HDL SRB-1 extent of postprandial lipaemia may also impact on vascular
dysfunction,4 and may thus be of major importance as a thera-
Ap

CETP CETP
oE

oE
,C
-1

peutic target for the development of drugs, and diet and lifestyle
Ap
1

CM CMR LRP-R
strategies to prevent cardiovascular disease.

Lipoprotein lipase Endogenous lipid pathway

Intestine The production and secretion of VLDL from the liver is largely
driven by the supply of lipid substrates for the synthesis of TAG.
Apo, apolipoprotein; CE, cholesteryl ester; CETP, cholesteryl ester transfer Lipid is supplied to the liver in the form of remnant lipoproteins
protein; CM, chylomicron; CMR, CM remnant; HDL, high-density lipoprotein;
LCAT, lecithin : cholesterol acyl transferase; LDL, low-density lipoprotein; (CMRs, VLDL remnants), non-esterified fatty acids from adipose
LDL-R, LDL receptor; LRP-R, LDL receptor-related protein receptor; SRB-1, tissue and, to a lesser extent, by de novo lipogenesis (synthesis of
scavenger receptor B-1; TAG, triacylglycerol; VLDL, very low-density lipoprotein.
TAG predominantly in humans). The synthesis of VLDL is
similar to that of CM, in that it also occurs in two stages involving
Figure 2 the fusion of a nascent VLDL particle with a lipid droplet. In

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 BASIC SCIENCE

common with the exogenous pathway, the secretion of VLDL is cholesterol and CHD risk. HDL is synthesized in the gut and liver,
also followed by the sequential lipolysis of TAG by LPL and and increases its particle size in the circulation as a result of the
generation of VLDL remnants, intermediate-density lipoprotein acquisition of cholesterol from two principal sources: the surface
(IDL), and eventually LDL. Remnants of VLDL, IDL and LDL bind material released from TAG-rich lipoproteins (CMs and VLDL)
to another receptor in the liver which recognizes both apo E, during LPL-mediated lipolysis, and from peripheral tissues. This
exclusively in VLDL remnants and IDL, and apo B-100 in LDL, explains, in part, why patients with low plasma TAG, who can
namely the LDL receptor. Unlike the LRP receptor, the LDL re- lipolyse TAG efficiently, often have raised plasma HDL choles-
ceptor is subject to sensitive feedback control that regulates terol and are at lower risk of developing coronary disease. It also
intracellular and extracellular cholesterol levels. Approximately provides another example of the metabolic interdependency of
60% of LDL is removed from the circulation by the LDL receptor, TAG-rich lipoproteins and HDL. The particles responsible for the
while the remainder is internalized into cells via scavenger re- efflux of free cholesterol from cells are very small, pre-b HDL
ceptors, a route that has been associated with the accumulation particles composed of phospholipid and apo A-I. Cholesterol
of LDL in atherosclerotic lesions. The metabolic fate of VLDL, efflux is facilitated by membrane-bound efflux proteins (adeno-
whether it is removed as a remnant or transcends to IDL and sine triphosphate-binding cassette proteins), and by the forma-
LDL, largely depends on its size and lipid composition. Larger, tion of a free cholesterol gradient from the cell across the cell
TAG-rich VLDL is less likely to be converted into LDL and is membrane to pre-b HDL. The latter is generated by the re-
removed as partially delipidated VLDL remnants, whereas esterification of free cholesterol by the enzyme lecithin: choles-
smaller VLDL is a precursor of LDL and is often referred to as terol acyltransferase, and the migration of these newly formed
‘pre-LDL’. cholesterol esters into the hydrophobic core of immature discoi-
dal HDL into what becomes mature, spherical HDL. The newly
The low-density lipoprotein receptor pathway acquired cholesterol ester is transported back to the liver either
directly by HDL, which is not internalized but donates its
All cells, but most notably liver cells, have a highly developed
cholesterol esters through binding to a specific liver receptor
and sensitive mechanism for regulating intracellular and
(SRB-1), or indirectly via transfer of its cholesterol esters to apo
intravascular levels of cholesterol. The liver synthesizes
B-containing lipoproteins (VLDL, LDL) via a shuttle protein called
approximately 500 mg cholesterol a day but imports the same
cholesterol ester transfer protein. The microcirculation of the
quantity from the blood in the form of LDL. When stressed,
liver contains another endothelial lipase, and close relative of
cells will always import cholesterol in order to save energy.
LPL, called hepatic lipase. This enzyme effectively punches a hole
Cholesterol is acquired by the cell through the uptake and
in the surface phospholipid of HDL to facilitate access to the lipid
degradation of lipoproteins, but chiefly LDL particles. As the
core and delivery of cholesterol ester to the hepatocyte. Inter-
requirement for cholesterol increases within the cell, it in-
estingly, the activity of hepatic lipase is inhibited by oestrogens,
creases its production of LDL receptors, more LDL is removed
which explains, in part, why women have a higher concentration
from the blood and serum cholesterol falls. Conversely, if the
of cardioprotective HDL than men throughout their lives.
cell becomes overloaded with cholesterol, the production and
thus activity of LDL receptors falls, and serum LDL increases.
In fact, in the complete absence of LDL, cells have the capacity What is the most important source of lipid-mediated
to manufacture sufficient cholesterol to meet their metabolic cardiovascular risk?
needs. The activity of the LDL receptor is regulated by the The absolute risk associated with raised serum LDL cholesterol is
intracellular level of free cholesterol. Thus, anything that in- well founded, and rises steeply with increasing concentration of
creases free cholesterol within the cell will inadvertently lower LDL. However, for the majority of individuals this is about 20%.
serum LDL cholesterol. Low intracellular free cholesterol Much greater risk in populations can be attributed to moderately
stimulates this mechanism by causing the release of a sterol raised serum TAG arising from an impaired clearance of CMRs
regulatory element-binding protein (SREBP), a nuclear tran- and VLDL and/or overproduction of VLDL. This aberration in the
scription protein that binds to DNA and switches on the tran- metabolism of TAG has the knock-on effects of increasing the
scription of the LDL receptor gene. This effect is accompanied number of small, dense LDL particles with increased atherogenic
by an increase in cholesterol synthesis in the cell via activation potential, and lowering the concentration of cardio-protective
of 3-hydroxy-3-methylglutaryl-CoA reductase, and an increase HDL, a dyslipidaemia known as an atherogenic lipoprotein
in the re-esterification of cholesterol for storage as cholesterol phenotype (ALP).6 An ALP is the most common finding in pa-
esters. The discovery of the LDL receptor pathway by Brown tients with existing CHD and at risk of CHD, and its prevalence
and Goldstein in the 1970s5 provided a molecular mechanism promises to increase with the exponential growth of obesity and
by which to explain the metabolic basis of hypercholestero- type 2 diabetes. A
laemia, and how certain dietary saturated fats and statins raise
and lower serum LDL cholesterol, respectively.

Reverse cholesterol transport: high-density lipoprotein

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3 Zilversmit DB. Atherogenesis: a postprandial phenomenon? Circulation FURTHER READING

1979; 60: 473e85. Frayn KN. Metabolic regulation: a human perspective. 3rd edn. Oxford:
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SURGERY 31:6 272 Ó 2013 Elsevier Ltd. All rights reserved.