Medium-chain triglyceride and n-3 polyunsaturated fatty
acid-containing emulsions in intravenous nutrition
Chan, Samuel; McCowen, Karen C; Bistrian, Bruce
Section Editor(s): Calder, Philip; Deckelbaum, Richard
Nutrition Support Service, Beth Israel Deaconess Medical Center, Harvard Medical
School, Boston, MA 02215, USA
Abstract
Introduction
Structure, biochemistry, and metabolism of long-chain triglycerides
Structure, biochemistry, and metabolism of medium-chain triglycerides
Metabolism of medium-chain triglycerides and n-3 polyunsaturated fatty
acid-containing emulsions
Current development
Conclusion
References and recommended reading
Abstract
Medium-chain triglycerides and n-3 polyunsaturated fatty acid emulsions as a
physical mixture have attracted increasing interest for use in parenteral
nutrition and may play an important role in the development of structured
triglycerides in a future generation of new lipids. Over the past two decades,
the clinical use of intravenous emulsion for the nutritional support of
hospitalized patients has relied exclusively on long-chain triglycerides
providing both a safe, calorically dense alternative to dextrose and a source of
essential fatty acids needed for biological membranes and maintenance of the
immune function. During the past decade, the development of new triglycerides
(medium- and long-chain triglyceride emulsions and structured triglyceride
emulsions) for parenteral use have provided useful advances and opportunities to
enhance nutritional and metabolic support. Medium-chain triglycerides and n-3
polyunsaturated fatty acid emulsions possess unique physical, chemical, and
metabolic properties that make them theoretically advantageous over the
conventional long-chain triglycerides. The physical mixture of medium- and
long-chain triglycerides have been used clinically in patients with critical
illness, liver disease, immunosuppression, pulmonary disease, and in premature
infants, with good tolerance and the avoidance of some of the problems
encountered with long-chain triglycerides alone.
---------------------------------------------Abbreviations; ALA [alpha]-linolenic acid; DHA docosahexaenoic acid; DHLA
dihomo-[gamma]-linolenic acid; EFA essential fatty acid; EPA eicosapentaenoic
acid; LCT long-chain triglycerides; LPL lipoprotein lipase; MCT medium-chain
triglycerides; PUFA polyunsaturated fatty acids; VLDL very low-density
lipoproteins
Introduction
Dietary lipids are efficient fuels for many tissues of the body and can be used
to prevent or correct essential fatty acid (EFA) deficiency. Lipids are an
important energy source in critically ill patients because of their high energy
density, low osmolarity, and preferred utilization during the systemic
inflammatory response [1]. Lipid emulsions have been designed based on the model
of the chylomicron, with a triglyceride core and a surface layer of phospholipids.
This results in lipid emulsions containing two different particle populations
that consist either of triglyceride-rich or phospholipid-rich particles. The
metabolism of lipid emulsions involves both types of particles. In the USA, the
commercially available intravenous fat emulsions contain long-chain triglycerides
(LCT) derived from either soybean or a mixture of soybean and safflower oil, and
phospholipids from either egg yolk or soy. A second type of triglyceride which
can be given parenterally is a medium-chain triglyceride (MCT) consisting
principally of saturated fatty acids of either 6 or 8 carbons esterified to
glycerol. MCT are derived from coconut, palm, and palm kernel oils by physical
separation [2,3]. A physical mixture emulsion composed of MCT and LCT is
available in Europe and much of rest of the world but is not yet available in
the USA. A structured lipid emulsion, derived by transesterification of MCT and
LCT to produce a chemical mixture of medium and long-chain fatty acids
esterified to glycerol in a random manner, has just been released in Europe.
Polyunsaturated fatty acids (PUFA) are long-chain monocarboxylic organic acids
with two or more double bonds in their molecule. In humans, the enzymes for
desaturation can only place the first double bond between carbons 9 and 10
counting from the methyl (omega) end to produce the n-9 family of PUFA. n-6 and
n-3 PUFA are derived from two EFAs, linoleic and [alpha]-linolenic, which are
deemed essential because of the inability of humans to desaturate at these
positions. Linoleic acid is a n-6 PUFA found in high concentrations in vegetable
oil (soybean and safflower). The main end-products of interest include
dihomo-[gamma]-linolenic acid (DHLA) and arachidonic acid from linoleic acid and
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from [alpha]-linolenic
acid (ALA) through elongation and two desaturations, delta-6 and delta-5 (Fig.
1) [4]. DHLA and arachidonic acid can serve as precursors for eicosanoid
production, one-series prostanoids from DHLA and two-series prostanoids and
four-series leukotrienes from arachidonic acid. A high concentration of n-6 PUFA
in the diet has been shown to influence neutrophil and macrophage function
negatively and to impair reticuloendothelial system clearance [5-7], and
decrease the rate of bacteria clearance in sepsis [8]. ALA is the central member
of the n-3 family of fatty acids which serves as a precursor for EPA and DHA,
the former of which forms three-series prostanoids and five-series leukotrienes
that are less potent than their respective two- and four-series counterparts.
Although preformed EPA more rapidly influences the tissue phospholipid content
and immune function in animal studies [9], the clinical use of ALA in an
immune-enhancing formula in trauma patients was effective at reducing the
infectious risk [10] similar to the result with fish oil in critically ill
patients [11]. Fish oils contain very little n-6 PUFA but can contain a
significant amount of n-3 PUFA as EPA and DHA, particularly in fish from cold
water.
Lipids are incorporated into membrane phospholipids to modulate the cell
responses to various stimuli, and to influence several intracellular metabolic
processes when they influence signalling efficiency, or in the case of
arachidonic acid act as a second messenger. They also directly or indirectly
influence the production and action of important mediators, the eicosanoids.
Such properties can influence inflammatory and thrombotic responses, tissue
microperfusion, whereas other components may affect resistance to perioxidative
attacks. Certain of the n-3 and n-6 fatty acids (EPA, DHLA and arachidonic acid)
serve as precursors for the eicosanoids which are ubiquitous second messengers,
are second messenger themselves or have unique effects (DHA in vision and brain
function) [1]. These three families of fatty acids have numerous interrelationships.
For example, [alpha]-linolenic acid can be converted in the human to EPA or DHA
but with limited efficiency, making this a less rapid and effective means of
increasing the EPA content of a membrane. EPA has a much greater impact on
arachidonic acid concentration in tissue membrane phospholipids, although
[alpha]-linolenic acid inhibits the elongation and desaturation of linoleic acid
to DHLA and arachidonic acid. The three principal families, n-3, n-6, and n-9,
in human metabolism have as their starting compounds for elongation and
desaturation an 18-carbon unsaturated fatty acid, ALA, linoleic acid and oleic
acid, respectively. The enzymes of desaturation and elongation of 18-carbon
fatty acids are principally in the liver and have as their order of preferred
substrate n-3>n-6>n-9. Small amounts of linoleic acid thus prevent the
elongation and desaturation of oleic acid (18 : 1n9) to mead acid (20 : 3n9),
which is only found in EFA deficiency. ALA, which is generally found in limited
amounts except in soybean oil, canola oil, and linseed oil, will not be
inhibited by large amounts of linoleic acid in the diet, allowing for the
production of EPA and DHA. Finally, EPA inhibits the elongation and desaturation
of linoleic acid to arachidonic acid. The only other conditions in which
arachidonic acid is substantially reduced in amount in serum and presumably
membrane phospholipid are prematurity as a result of immature enzyme systems
[12], end-stage liver disease due to impairment of their enzymes [13], and EFA
deficiency.
Structure, biochemistry, and metabolism of long-chain triglycerides
LCT emulsions are mixtures of highly polyunsaturated triacylglycerols that
contain 16-18 carbon atoms, derived principally from soybean oil. LCT is a
preferred fuel in the critically ill with maximum benefit at approximately
10-15% of total energy [14,15]. LCT improve nitrogen balance as effectively as
carbohydrate and also reduce triglyceride accumulation in critically ill
patients, presumably by limiting de-novo lipogenesis [16]. The administration of
parenteral LCT emulsions can impair the function of the reticuloendothelial
system when given in excessive amounts or too rapidly [6,7]. This has been
considered to be responsible for increased morbidity caused by infection, in
patients receiving preoperative or post-trauma total parenteral nutrition
containing fat compared with glucose and amino acids alone as the energy source
[17,18*]. This adverse effect has only been seen when lipid is infused at rates
greater than total energy expenditure (0.11 g/kg per hour) [2].
Structure, biochemistry, and metabolism of medium-chain triglycerides
MCT are triacylglycerols that contain saturated fatty acids of 6-10 carbon atoms
[18*] derived from the physical separation of tropical oils, which removes most
lauric acid and other long-chain fatty acids to leave chiefly caprylic and
capric acids in a ratio of approximately 2 : 1. MCT possess several unique
physical, chemical and structural characteristics that make them a more
desirable substrate. MCT are water soluble [19] and are rapidly hydrolysed and
absorbed from the intestinal lumen, because they do not require the presence of
bile and pancreatic lipase. They do not require micelle formation before
absorption, and are absorbed as medium-chain fatty acids bound to albumin in the
portal vein. The half-life of MCT in plasma is approximately 17 min compared
with 33 min for LCT [20]. MCT are not stored in adipose tissue to any significant
extent with either enteral or parenteral nutrition and do not accumulate in the
liver [20]. More importantly, MCT do not promote the synthesis of eicosanoids
(prostaglandins, thromboxanes, and leukotrienes) nor do they serve as precursors
for oxygen free-radical production, both of which may adversely affect
reticuloendothelial system function and amplify systemic inflammatory responses,
especially in the critically ill [21]. Finally, MCT have a thermogenic effect
due to their more efficient and obligate oxidation and decreased likelihood of
being stored when compared with an equivalent amount of LCT [22]. Despite the
overall increase in total energy expenditure, their nitrogen-sparing effects are
preserved compared with LCT in equivalent amounts.
MCT are more readily oxidized than LCT, and they do not require the carnitine
transport system for mitochondrial entry [23]. Patients with severe liver
dysfunction have reduced synthesis of albumin, carnitine, hepatic triglyceride
lipase, phospholipase, lecithin cholesterol acyl transferase and apoprotein
C-II, the latter which is required for lipoprotein lipase activity [24]. Lipid
emulsions containing both MCT and LCT are an ideal source of fat for such
patients because they meet the increased requirement for fatty acids as energy
as medium-chain fatty acids, with their limited need for these accessory
components and preferential hydrolysis, and they also provide EFAs for their
depleted stores, which improves the efficiency of protein and energy utilization.
MCT cause a lesser impairment of Kupffer cell function, because they are cleared
more rapidly from the blood stream, are oxidized preferentially and metabolized
independently of carnitine [25]. MCT provides readily oxidized fat, and it may
therefore cause a reduction in hepatic side-effects such as cholestasis,
steatosis, or fatty liver during parenteral nutrition, because some of these
benefits have been seen in animal studies [16], and such characteristics might
be particularly important for patients with cirrhosis [26].
MCT oxidation is also less affected by glucose and insulin than is the oxidation
of LCT. MCT foster ketogenesis and require insulin to control this pathway in
type I diabetes mellitus patients. In a clinical study [27] of patients
undergoing hepatic resection, perioperative feeding with total parenteral
nutrition including MCT : LCT emulsion showed reduced infectious morbidity and
improved hepatic function. MCT is formulated for parenteral nutrition [28] in
physical mixtures or as a component of structured lipids. Physical mixtures are
lipid emulsions characterized by the partial replacement of LCT with MCT on a
percentage basis. Structured lipids are synthetic compounds made up of both
medium- and long-chain fatty acids bound on the same glycerol molecule in a
predetermined proportion to form a structured triglyceride [29,30]. These
'designer lipids' provide fuel as well as meeting EFA requirements. At the
present time, physical mixtures are commercially available in Europe and much of
the world except the USA, and structured lipids have just been introduced
commercially in Europe.
Metabolism of medium-chain triglycerides and n-3 polyunsaturated fatty
acid-containing emulsions
Intravascular lipid emulsion metabolism is similar to the metabolism of
triglyceride-rich chylomicron. Both lipid emulsion particles and chylomicrons
have a triglyceride core that is stabilized by a surface layer of phospholipids.
Despite the absence of apolipoprotein in the lipid emulsion, apoproteins (apo)
and lipoprotein lipase (LPL) play an important role in the regulation of
intravascular lipid emulsion metabolism. Apo C and E are rapidly acquired from
the high-density lipoprotein by the emulsion particles as a first essential
regulatory step. Apo C-II and apo C-III modulate the binding of emulsion
particles to the receptor site of lipoprotein lipase and activate this enzyme
[24]. Apo E enhances the uptake of triglyceride-rich lipoprotein particles and
modulates the cellular metabolism of both triglyceride and cholesteryl ester
after particle internalization [31]. Subsequently, emulsion particles bind to
LPL at the endothelium site of most extrahepatic tissue. The reduction of
triglyceride content and the size of emulsion particles is regulated by the
hydrolysis of emulsion triglycerides by LPL. Presumably the fatty acyl
composition of emulsion triglycerides markedly influences the hydrolysis.
MCT are hydrolysed much faster than LCT, because MCT are more soluble at the
surface of emulsion particles [32]. Triglycerides containing long-chain n-3 PUFA
are reportedly hydrolysed by LPL at a much slower rate than soy LCT. MCT/LCT
physical admixtures were found to clear faster than LCT due to faster peripheral
hydrolysis by LPL and the rapid removal of remnant particles and their
constituents. Fatty acids on hydrolysis of the core triglyceride of emulsion
particles are either released into the circulation to increase the free fatty
acid pool or are immediately taken up by the adjacent tissue. Through exchanges
of neutral lipids mediated by the cholesteryl ester transfer protein, emulsion
particles transfer triglycerides to endogenous cholesterol-rich high- and
low-density lipoproteins and acquire cholesteryl ester [33]. MCT-containing
emulsions appear to transfer more triglycerides and receive fewer cholesteryl
esters compared with LCT. The n-3 PUFA do not substantially affect neutral lipid
exchange due to the marked inhibition of lipolysis by LPL [34].
The final step of intravascular metabolism of lipid emulsion consists of
cholesteryl ester-enriched and triglyceride-depleted remnant particle uptake by
the liver and extrahepatic tissues. Hepatic lipase regulates this process in the
liver [32,35]. Liver uptake of triglycerides and cholesteryl esters stimulates
the hepatic production of apo B-100 and the release of very low-density
lipoproteins (VLDL). VLDL can then be metabolized to low-density lipoproteins.
Apo E and lipoprotein lipase present on emulsion remnants [36] and proteoglycans
and remnant receptors on cell membranes regulate the tissue uptake of emulsion
remnants. The presence of certain fatty acids at the sn-2 position of triglycerides
may markedly influence hydrolysis and particle uptake [37,38]. The sn-2 fatty
acids are also preferentially preserved as components of chylomicrons and VLDL
particles for ultimate incorporation in tissue membranes [39]. Therefore, the
fatty acids at the sn-2 position may be vitally important in the design of new
types of structured triglycerides containing different types of both medium- and
long-chain fatty acids on the same glycerol backbone.
Current development
Future clinical studies with MCT and n-3 PUFA-based emulsions, whether physical
mixtures or structured lipids, should have clear outcome objectives sufficient
to prove their theorized metabolic superiority. Lipid emulsions derived from
soybean oil contain substantial quantities of PUFA, mainly linoleic acid, and
insufficient amounts of antioxidants. Their too rapid infusion can lead to an
unbalanced fatty acyl pattern in cell membrane phospholipids and is associated
with an increased production of peroxidative catabolites. The goal of some
proposed and future preparations is to better maintain the fatty acyl balance in
membrane phospholipids, to take advantage of a selective enrichment in n-3 PUFA,
and to maintain or restore a suitable antioxidant status.
Membrane phospholipids contain EFAs and the n-3 and n-6 PUFA ratio may
substantially alter cellular metabolism. The triacylglycerol pattern influences
the physical properties of cell membranes such as the fluidity and permeability,
the activity of membrane receptors, enzymes, and ion channels, as well as the
cellular response to various physical or chemical stimuli, through the formation
of selective secondary messengers. The addition of n-3 PUFA providing EPA
compete with arachidonic acid to produce eicosanoids under the action of
cyclooxygenase and lipoxygenases which are less inflammatory and non-thrombogenic
[40]. These properties have a clear implication for reducing inflammation,
infection, and thrombotic morbidity in such conditions as adult respiratory
distress syndrome, nosocomial infection, and vascular thrombosis [41,42].
The n-3 PUFA may blunt the response to endotoxin and modulate undesirable
sequelae to sepsis [43] by decreasing the production of inflammatory cytokines
such as IL-1 and TNF from stimulated mononuclear cells and reduce the sensitivity
of peripheral target cells to the potent inflammatory and catabolic effects of
these mediators [39,41,44]. The complexity of n-3 PUFA effects on inflammation
and immune function reflects their multiple sites of actions, including the
alteration of membrane composition and eicosanoid and cytokine production. In
models of endotoxemia using infusions of endotoxins (lipopolysaccarides), n-3
PUFA supplementation reduces lactic acidosis, maintains or improves perfusion
and microcirculation in several important organs including the intestine, heart,
and lung [45-49]. In a model of chronic sepsis, dietary n-3 PUFA decreased
mortality as a result of the decreased production of prostaglandin E2 by Kupffer
cells [25]. An enhancement of cellular immunity and macrophage function through
a decrease in the production of prostaglandin E2 by macrophages was observed in
the model of hemorrhagic shock [50]. An improvement in survival was reported not
only in experimental but also in clinical organ transplantation [51,52]. This is
caused by an adequate microperfusion maintained in the grafted organ, together
with a protection against excessive inflammatory reaction and also a controlled
immune response via a downregulation of IL-2-dependent T-cell activation [53].
Although animal models have given contrary results on the effect of n-3 PUFA in
models of infection, human studies in cancer patients [54,55], the critically
ill [41], trauma patients, IgA nephropathy, ulcerative colitis, and remission
rates in regional enteritis have all showed positive benefits [39,56]. These
human studies have all been conducted employing enteral administration, which
made study easier because of the drug status of parenteral n-3 PUFA emulsions.
One presumes that similar effects to modulate the inflammations and immune
complex will be achieved by parenteral administration, but this will require
study. Although long-chain fatty acids when provided enterally are absorbed as
chylomicrons via the lymphatics to ultimately reach the systemic circulation,
the portal transport of n-3 PUFA does occur, which may influence metabolism to a
substantial degree [57].
In the critically ill patient, the MCT : LCT physical admixture may be useful as
obligate fuel and to limit net hepatic lipogenesis. In addition, compositional
changes induced by dietary supplementation of n-3 PUFA are often slow to obtain
optimal effects, although continuous enteral feeding does rapidly alter membrane
composition [40], and the possibility of intervening faster by intravenous
infusions is quite appealing. Infusion in normal subjects of an emulsion
containing 50% MCT, 40% soybean LCT, and 10% fish oil was associated with a
rapid triglyceride elimination and avoided lipid accumulation in plasma [59]. A
substantial improvement in muscle mass, cell-mediated immune response, and
metabolic expenditure were observed in a model of burned rat [60]. Lipid
emulsions may also serve as carriers for fat-soluble antioxidant vitamins such
as [alpha]-tocopherol or [beta]-carotene both to avoid depletion as well as to
maintain an adequate vitamin E status [61,62].
Conclusion
MCT and n-3 PUFA emulsions as a physical mixture have attracted increasing
interest for use in parenteral nutrition and may play an important role in the
development of structured triglycerides in a future generation of new lipids.
Over the past two decades, the clinical use of intravenous emulsion for the
nutritional support of hospitalized patients has relied exclusively on LCT
providing both a safe, calorically dense alternative to dextrose and a source of
EFAs, needed for biological membranes and maintenance of the immune function.
During the past decade, the development of new triglycerides (MCT : LCT
emulsions and structured triglyceride emulsions) for parenteral use have
provided useful advances and opportunities to enhance nutritional and metabolic
support. MCT and n-3 PUFA emulsions possess unique physical, chemical, and
metabolic properties that make them theoretically advantageous over conventional
LCT. The physical mixture of MCT and LCT have been used clinically in patients
with critical illness, liver disease, immunosuppression, pulmonary disease, and
in premature infants, with good tolerance and the avoidance of some of the
problems encountered with LCT alone [6,26,63]. The MCT and n-3 PUFA-containing
emulsions, either as physical mixtures or structured lipids, may be best suited
for selected patient populations who would benefit particularly from modulation
of the inflammatory response, such as those with severe adult respiratory
distress syndrome [42]. The determination of optimal lipid composition when
formulating a complete nutrient admixture to achieve these goals of providing
noncarbohydrate energy EFAs, optimal lipid clearance and modulation of certain
cell functions and metabolism will require much thought and considerable testing
in humans before clinical application.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
* of special interest
** of outstanding interest
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