Current Drug Metabolism, 2012, 13, 000-000 1?
1389-2002/12 $58.00+.00 © 2012 Bentham Science Publishers?
Uptake and Metabolism of the Short-Chain Fatty Acid Butyrate, a Critical Review of
Stuart M Astbury and Bernard M Corfe*
Molecular Gastroenterology Research Group, Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield,
Beech Hill Road, Sheffield, S10 2JF
Abstract: Butyrate is a short-chain fatty acid (SCFA) formed by bacterial fermentation of fibre in the colon, and serves as anenergy
source for colonocytes. The action of butyrate as a histone deacetylase inhibitor (HDACi) has led to a number of clinical trials testing its
effectiveness as a potential treatment for cancer. The biology of butyrate transport is therefore relevant to both its physiological and
pharmacological benefits. This review of the literature was carried out to assess the evidence for both the uptake and metabolism of bu-
tyrate, in an attempt to determine possible mechanism(s) by which butyrate can act as an HDACi. It is noted that although uptake and
metabolism are well characterised, there are still significant gaps in the knowledgebase around the intracellular handing of butyrate,
where assumptions or dated evidence are relied upon.
The short-chain fatty acid (SCFA) butyrate is formed via the
bacterial fermentation of non-starch polysaccharides (NSP) such as
fibre, in the colon. In comparison to other SCFA, butyrate is pre-
dominantly metabolised in the colon (with small concentrations
utilised by the liver and kidneys), whereas SCFA such as acetate
and propionate will pass into the peripheral circulation [1,2,3]. A
considerable body of literature has been built up based around the
effect of butyrate on colonocytes, with regard to its role as an in-
hibitor of histone deacetylase(HDACi) enzymes and related actions
(for a complete review of the colonic effects of butyrate see ).
The action of butyrate as anHDACi has led to a number of clinical
trials testing its effectiveness as a potential treatment for cancerat a
range of sites, including in combination with other drugs [5,6,7]. As
butyrate appears to have distinct effects as a metabolite and a drug,
we have sought to review the available literature to assess the evi-
dence at reaction level for both the uptake and metabolism of bu-
tyrate, in order to provide predictive data on the potential bystander
effects of the pharmacological application of butyrate. This forms
part of an ongoing effort in our team to unify the divergent effects
of butyrate .
The analysis of the metabolism of butyrate is broken down into
three principal areas: uptake, intracellular handling and b-oxidation.
Concluding comments include considerations for the application of
butyrate as a pharmacological agent and future research.
Searching was carried out using the manually-curated pathway
databases the Kyoto Encyclopedia of Genes and Genomes , and
Reactome . The relevant reactions were mined for references
and the articles pooled with those found in KEGG. Detailed search
terms were not required initially; butyrate/butanoate/butyric acid
was sufficient to locate the relevant pathways, which could then be
followed sequentially. Relevant papers, particularly those contain-
ing the first description of the reaction in question were then cita-
tion searched using ISI Web of Science and Google Scholar to find
papers not covered by KEGG and Reactome, and ideally to build up
a trail of experimental evidence.
*Address correspondence to this author at the Molecular Gastroenterology
Research Group, Academic Unit of Surgical Oncology, Department of On-
cology, University of Sheffield, Beech Hill Road, Sheffield, S10 2JF;
Tel: +44 (0) 114 271 3004; E-mail: email@example.com
gather more mechanistic data for each reaction. Finally, Medline,
ScienceDirect and Google Scholar were searched using the same
search terms in combination with butyrate/?-oxidation to find pa-
pers not indexed by Reactome, KEGG and UniProt. Where over-
lapping and redundant enzyme names were used, the BRENDA
enzyme database was used as source information for resolving dif-
The Universal Protein Resource (UniProt) was searched to
Evidence for the uptake of butyrate (as well as other short-chain
fatty acids) into the cell is split between simple, non-ionic diffusion
across the plasma membrane, and diffusion facilitated by a number
of membrane proteins. Early studies favour the simpler model;
Walter & Gutknecht conducted a study on permeability constants of
various SCFAs using labelled 14C to measure flux across synthetic
membranes, and found constants they felt were consistent with non-
ionic diffusion . This model is still argued today, Kamp &
Hamilton conducted a review of the literature in 2006 and con-
cluded that rapid, passive diffusion was still the most convincing
model of transport for SCFA . Conversely, the above studies
are contradicted (at the earliest) by Phillips &Devroede, who in
1979 suggested that whilst butyrate can pass through lipid bilayers
via simple diffusion, the rapid dissociation to the butyrate anion
means facilitated diffusion must also take place [13,14]. Therefore,
although free diffusion of fatty acids may take place, it has very
little physiological relevance to the uptake of butyrate.
Accordingly, a considerable body of evidence now exists which
suggests that SCFA are predominantly taken up via a facilitated
process involving a number of transport proteins. The relatively
recent characterisation of a number of transmembrane proteins has
lead to two well defined routes of uptake, both monocarboxylate
transport proteins – MCT1, a hydrogen coupled transporter, and
SMCT1, a sodium coupled transporter. Butyrate also appears to
interact with a number of G protein coupled receptors; these will be
The Monocarboxylate Transporters
Following its initial molecular characterisation and designation
as monocarboxylate transporter, isoform 1 (MCT1) , a number
of studies were carried out in order to assess the role of butyrate as
a potential substrate. Initial studies describing the uptake of bu-
tyrate  consisted of first isolating luminal membrane vesicles
from donor colon tissue, followed by incubating them with labelled
2 Current Drug Metabolism, 2012, Vol. 13, No. ??
Astbury and Corfe
14C butyrate. The study clearly demonstrates an association between
butyrate uptake and HCO3
hence increased uptake. This study also contradicts the free-
diffusion model of uptake, with a 50-fold change in proton gradient
between intracellular and extracellular spaces leading to no signifi-
cant change in butyrate diffusion. The aforementioned study is also
consistent with earlier research on rat distal colon, incidentally 14C
butyrate uptake was found to be mediated by a HCO3
fore the characterisation of the MCT family .
Following this research, the role of MCT1 in mediating butyrate
uptake was further studied via assessing uptake in diseased colonic
tissue - mainly samples from patients suffering from inflammatory
bowel disease (IBD), familial adenomatous polyposis (FAP) or
colorectal cancer. A study conducted by Thibaultet al. compared
tissue samples donated by 23 IBD patients, and samples from rats
with induced ulcerative colitis with healthy controls. In both study
groups MCT1 mRNA was dramatically reduced, with this reduction
correlating with the amount of inflammation. Functionally this was
demonstrated by a reduction in butyrate uptake as well as metabo-
lism . However, studies of MCT1 expression in colorectal can-
cer contradict this, with a study on 126 CRC tissue samples show-
ing upregulation of MCT1 (as well as isoforms 2 and 3) compared
to healthy surrounding tissue. A hypothesis has been proposed to
explain this: increased cell division leads to an upregulation of gly-
colysis; thus an increase in MCT1 expression provides a route for
lactate to leave the cell . These findings have also been repli-
cated . Therefore, although the role of MCT1 in butyrate uptake
- gradient, with imposition of increased
- leading to increased exchange with butyrate and
- gradient be-
is assured, further research is needed to determine how this is al-
tered in inflammatory bowel disease, and particularly cancer.
SLC5A8 and the Sodium-coupledmonocarboxylate Transporter
A possible additional route of butyrate uptake was discovered
in 2003 with the characterisation of the SLC5A8 gene, along with a
corresponding sodium-linked transporter protein . Due to the
high level of expression of this transporter in the colon, as well as
its observed downregulation during colorectal cancer, studies on
butyrate as a candidate substrate soon followed. The function of this
Na+cotransporter was determined via expressing the protein in an
animal model (the Xenopuslaevisfrog). The transporter was found
to bind a number of monoxarboxylates, including butyrate, and was
therefore named SMCT1 (sodium-linked moncarboxylate trans-
A comparison of the affinities of MCT1 and SMCT1 receptors
via Km value highlights an interesting issue. MCT1 has been found
to have a Km of 9 – 12mM [23,24] whereas SMCT1 gives far lower
values of 50-100μM . Higher Km values have been found for
SMCT1 (~1400-2300μM), but in a sample sourced from brain tis-
sue . Given that the physiological concentration of butyrate in
the colon reaches ~50mM , SMCT1 appears to have an ex-
tremely high affinity for butyrate relative to normal concentrations.
There could be a number of reasons for this; the high affinity means
that the vast majority of circulating butyrate will be taken up by
tissues expressing SMCT1 (i.e. the colon and kidney), thus limiting
any possible adverse affects to cells in other tissues. The relatively
low Km also means that the Vmaxof SMCT1 is reached quickly,
which will serve to limit uptake of butyrate; this hypothesis is an
Fig. (1). Summary of mechanisms and knowledgegaps for butyrate uptake and metabolism.
Butyrate is taken across the plasma membrane by two active mechanisms, MCT-1 and SMCT-1. The intracellular management of butyrate is unclear – through
active transport by a mitochondrial MCT-1, through free diffusion and thrgh cytosolic ligation to coA-SH and uptake of butyryl:coA.
Uptake and Metabolism of the Short-chain Fatty Acid Butyrate Current Drug Metabolism, 2012, Vol. 13, No. ?? 3
attractive one due to butyrate’s effects on cell division via HDAC
This evidence, coupled with the fact that SMCT1 is coupled to
a Na+ concentration gradient, means there is a far greater “push” of
butyrate into the colonocytes compared to via MCT1. MCT1 relies
on a H+ gradient, and as the magnitude of this gradient across the
apical membrane is negligible, there is a smaller driving force push-
ing butyrate across . However, the role of MCT1 in the uptake
of butyrate cannot be ignored, with some evidence showing that
butyrate concentrations, as well as other dietary constituents will
regulate the expression of the receptor itself [23,28,29].
The fact that SMCT1 is a sodium-coupled transporter provides
a mechanism by which butyrate and other SCFA can modulate
hydration, with Na+ uptake influencing Cl- and water absorption via
electrochemical gradient. This appears to be an identical mecha-
nism to the influence of glucose on intestinal H2O uptake (as util-
ised in oral rehydration therapy), however the effect of butyrate is
likely to be less profound [30,31].
With regard to SMCT1 functioning as a tumour suppressor, the
published evidence is compelling. The SLC5A8 gene was high-
lighted in the aforementioned paper  as a tumour suppressor
gene coding for a sodium transporter before butyrate and other
SCFA were identified as substrates. Initial justification for this
hypothesis consisted of using MS-PCR to analyseSLC5A8 methyla-
tion (and therefore gene silencing) in primary colon tumours, as
well as matched samples of healthy mucosa. SLC5A8 methylation
was detected in 38/64 carcinoma samples, with 35 of these showing
no methylation in matched healthy tissue. These findings have also
been replicated [32,33]. Despite the clear association between
SLC5A8 and colon cancer progression, there is no current research
to suggest mechanistic links between this and butyrate, besides the
role of SMCT1 in uptake.
Other Routes of Metabolism: Free Fatty Acid Receptors
Whilst not a method of uptake, butyrate and other short chain
fatty acids have been shown to act on a number of G-proteins,
dubbed free fatty acid receptors or FFAR. Of the receptors currently
characterized, those of greatest interest are GPR41 and 43 (FFAR3
and FFAR2 respectively) and GPR109A . The effect of bu-
tyrate on these receptors is fairly well documented, with the salient
points outlined below. These 3 G-protein receptors have been found
to be expressed in the colon, with both GRP41 and GPR43 ex-
pressed on the apical membrane and mucosal layer, and GPR109A
found on the apical membrane [34,35]. However both GPR41 and
GPR43 are predominantly expressed on either leucocytes (GPR41
and GPR43) or adipocytes (GPR41 only) [27,36]. Therefore if bu-
tyrate is to have a significant effect on these receptors, there must
also be a mechanism for a molecule to pass out of the colonocyte
through the basolateral membrane to the adipose tissue or blood
vessels, currently such a mechanism has not been determined.
Descriptions of the function of these receptors are wide ranging
in the literature, both GPR41 and GPR43 have a role in calcium
homeostasis, with intracellular Ca2+ being mobilised on activation
by butyrate. Evidence suggests GPR41 is most sensitive to butyrate
in this regard, with GPR43 being more sensitive to acetate and
propionate [37,38,39]. GPR43 may also have a role in neutrophil
recruitment, thus providing a mechanism by which butyrate can
affect intestinal inflammation, however these findings have not
been replicated, and are based on a Gpr43 knockout study rather
than any dose-response relationship .
Functionally, GPR109A may be of most interest due to its role
as a tumour suppressor. Originally characterised as a receptor for
nicotinate, GPR109A also acts as a receptor for butyrate, albeit with
a low affinity. This makes it unremarkable given the low concentra-
tions of circulating butyrate, yet it becomes more significant when
the far higher concentrations in the colon are taken into account
(see above). As with SLC5A8, the gene coding for GPR109A is
silenced in colon cancer, also via DNA methylation. Re-expression
of the receptor in cancer cells induces apoptosis, but only in the
presence of nicotinate or butyrate, with the effects of butyrate ap-
parently being independent of any HDAC inhibition. These findings
have been confirmed in cell culture and a mouse model, although
replication of the findings is lacking [35,41].
ii. Intracellular Management of Butyrate
Following the simple and well-defined characterisation of the
uptake of butyrate, the intracellular management of butyrate involv-
ing its movement to the ?–oxidation pathways in the mitochondria
is less well clear. Longer-chain fatty acids (LCFA) are bound by
fatty acid binding proteins (FABP) following uptake and are ligated
to coenzyme-A (COASH) in the cytosol prior transport into perox-
isomes or mitochondria. This event may occur at the plasma mem-
brane or in the cytosol, however, no parallel mechanism has been
reported for butyrate and SCFA / MCFA in humans. A report sug-
gested the presence of aacyl-CoA synthetasein rat liver – providing
Table 1. Summary of key reaction steps and level of evidence available for each
Reaction step Location Enzyme(s) Evidence
Ligation of butyrate to butyryl-CoA Cytosol
Butyryl-CoA transferase, medium-
chain acyl-CoA synthetase (MACS).
Strong evidence for a broadly specific MACS
[49,51]. Some evidence for a narrowly specific
butyryl-CoA transferase .
Conversion of butyryl-CoA to
Short-chain acyl-CoA dehydrogenase
(SCAD), trans-2-enoyl-CoA reduc-
Strong evidence for SCAD [53,54,55,56]. Evi-
dence for trans-2-enoyl-CoA reductase lacking
in mitochondria, possibly peroxisomal .
Conversion of crotonyl-CoA to 3-
Mitochondria Enoyl-CoA hydratase
Strong evidence for broadly specific (C4-16)
Conversion of 3-hydroxybutyryl-
CoA to acetoacetyl-CoA
Short-chain acyl-CoA dehydrogenase
(SCHAD), hydroxyacyl-CoA dehy-
drogenase (HADH), 3-
Strong evidence for both SCHAD and HADH
[59,60,61]. 3-hydroxybutyryl-CoA dehydro-
genase not isolated in humans .
Butyrate is taken across the plasma membrane by two active mechanisms, MCT-1 and SMCT-1. The intracellular management of butyrate is unclear – through active transport by a
mitochondrial MCT-1, through free diffusion and thrgh cytosolic ligation to coA-SH and uptake of butyryl:coA.
4 Current Drug Metabolism, 2012, Vol. 13, No. ??
Astbury and Corfe
a route for the activation of medium- and short-chain fatty acids
before mitochondrial entry. When both mitochondrial and cytosolic
acyl-CoA synthetase enzymes were compared, using acetate and
propionate as substrates it was found that ~80% of acetate was me-
tabolised in the cytosol vs. the mitochondria, and ~40% of propion-
ate . However, no studies replicating this were identified
through literature searching, nor any using butyrate as a substrate.
This represents a key gap in the literature around understanding the
metabolism of butyrate as available evidence from LCFA metabo-
lism suggests most metabolic control is exerted through regulation
of entry of acyl-coA into the mitochondrion .
Movement from the Cytosol to the Mitochondria
As with entry across the plasma membrane, it is unclear
whether passage of butyrate across the mitochondrial membrane is
a free or facilitated event. A mitochondrial monocarboxylate trans-
porter would provide a convenient route for butyrate once it has
been taken up by the cell. Brooks et al.  purified an MCT1 iso-
form from the mitochondria of rat skeletal and cardiac muscle. Sub-
sequent studies have reported expression of mMCT-1 in human cell
lines and implicated it in the handling of excess lactate produced by
neoplastic glycolytic metabolism . The presence of a dedicated
tricarboxylate transport protein – solute carrier 25 A1 (SLC25A1)
 on human mitochondria is also of interest, especially given its
role in histone acetylation . Knockout of the sea gene, a
SLC25A1 ortholog in Drosophila results in extensive chromosome
breakage and cell cycle arrest – both consistent with a reduction in
histone acetylation. SLC25A1 knockout in human fibroblasts was
found to yield the same effects. A similar receptor for butyrate
would provide a suitable mechanism for mitochondrial transport as
well as inhibition of histone deacetylation, however none has been
iii. Metabolism – ?-oxidation
Once in the mitochondria, metabolism of a large proportion of
butyrate follows the ?-oxidation pathway, in which a fatty acid is
broken down to an acetyl-CoA molecule via a number of interme-
diate steps. Whilst being functionally identical, the pathway itself
will vary for the breakdown of each fatty acid with regard to the
enzymes required for each step. Prior to ?-oxidation butyrate must
be ligated to coenzyme A to formbutyryl-CoA.
Butyryl-CoA Transferase/acyl-CoA Synthetase
The earliest reports of a mammalian butyryl-CoA transferase
(also named butyryl-CoA synthetase/ligase) in the literature date
back to 1965, with the purification of a butyrate specific enzyme
from bovine heart mitochondria . Substrate specificity for this
enzyme was found to be different to the already characterised ace-
tyl-CoA synthetase. Citation searching using this initial paper re-
veals further efforts to determine the function and substrate speci-
ficity of this enzyme, all via non-human studies. Doubts as to there
being a human form of an chain-length specificbutyryl-CoA trans-
ferase quickly begin to appear, with enzyme assays showing multi-
ple overlap between butyrate and other SCFA or MCFA [49,50].
Aas&Bremner make the first mention of this overlap, with their
study showing butyryl-CoA synthetase metabolising SCFA with 3-
7 carbon atoms, as well as a separate acyl-CoA synthetase metabo-
lising SCFA with 4-12 carbon atoms. Based on the above studies, it
can be concluded that multiple enzymes are responsible for the
same function of attaching coenzyme A to butyrate: a broadly spe-
cific, ATP dependent medium-chain acyl CoA synthetase (MACS,
also MACS-2, XM Ligase, butyrylcoAsynthetase) [51,49]which
can ligate acyl chain lengths from C4-C11 to coA, as well as an
ATP independent butyryl-CoA transferase, which will also metabo-
lise acetate and succinate. Other acyl-coA ligases include MACS-4,
with preference for C6-C20 and acetate coA ligase with preference
for C2-C3. A further C3-specific propanoatecoA ligase has not
been reported in humans . The aforementioned papers suggest
that while butyryl-CoA transferase catalyses a reversible reaction,
the MACS will only catalyse the reaction in the forward direction.
Conversion of Butyryl-CoA to Crotonyl-CoA
The metabolism of butyryl-coA is better characterized than
upstream steps in butyrate metabolism, perhaps due to a greater
clinical significance - that of short-chain acyl-CoA dehydrogenase
(SCAD) deficiency, as well as the more common medium-chain
equivalent (MCADD). Thus, the evidence base for a short chain
acyl-CoA dehydrogenase enzyme is far more consistent in the lit-
erature after its initial discovery . The SCAD flavoprotein will
oxidise butyryl-CoA, reducing a flavin adenine dinucleotide (FAD)
molecule in the process. Later clinical studies have helped to con-
firm SCAD as having a role in butyrate metabolism – patients with
a deficiency excrete significant amounts of butyrate (as well as
other SCFAs), and studies using 14C labelled butyrate consistently
show marked decrease in catabolism of 40-60% vs. healthy controls
[54,55,56]. Compared to the somewhat lacking characterisation of a
human butyryl-CoA transferase enzyme, the clinical significance of
SCAD has meant its role in butyrate metabolism is confirmed.
The enzyme trans-2-enoyl-CoA reductase has also been found
to convert butyryl-CoA to crotonyl-CoA, reducing NAD+ (rather
than FAD) in the process. However, evidence for a mitochondrial
form of the enzyme is lacking. A trans-2-enoyl CoA reductase iso-
form is present in the peroxisome , however as the peroxisome
is responsible for the breakdown of very long chain fatty acids
(VLCFA, >22 carbon atoms) – this is likely irrelevant to butyrate
metabolism. Evidence for a mitochondrial form involved in fatty
acid breakdown is lacking, with research suggesting the enzyme in
fact catalyses the reaction in the opposite direction – i.e. as a part of
fatty acid synthesis .
Crotonyl-CoA represents a mid-point in the metabolism of bu-
tyrate, the molecule will then be oxidised to one more intermediate
– 3-hydroxybutyryl-CoA, before conversion to acetoacetyl-CoA, at
which point the metabolic pathway becomes identical to that of all
other fatty acid molecules. The reaction is catalysed by a non-
butyrate specific enzyme – enoyl-CoA hydratase, which will act on
fatty acids with 4-16 carbon atoms. The enzyme is well character-
ised, again due to its deficiency providing a convenient method of
studying the enzyme in humans. Two isoforms exist, one in the
peroxisome and one in the mitochondria. Deficiency of enoyl-CoA
hydratase leads to accumulation of fatty acids and deficient ?-
oxidation (as with SCAD deficiency).
Conversion of 3-hydroxybutyryl-CoA to Acetoacetyl-CoA
The final step in this pathway is the conversion of 3-
hydroxybutyryl-CoA to acetoacetyl-CoA (which will then be even-
tually oxidised to acetyl-CoA). As with some of the above steps,
this reaction is potentially catalysed by a number of enzymes, with
evidence varying for each. It can be assumed that at least two vari-
ants of 3-hydroxyacyl-CoA dehydrogenase exist: one for SCFA
(short-chain hydroxyacyl-CoA dehydrogenase, SCHAD), as well as
another hydroxyacyl-CoA dehydrogenase (HADH) with a wider
specificity for medium- and long-chain fatty acids. Both of these
are well characterised in humans [59,60,61]. Both will also catalyse
the above reaction in both directions, reducing a molecule of NAD+
in the forward direction.
Despite SCHAD displaying a high affinity for butyrate (in the
form of 3-hydroxybutyryl-CoA) , some efforts have been made
to characterise a purely butyrate specific enzyme – a “3-
hyroxybutyryl-CoA dehydrogenase”. A candidate enzyme was
isolated , albeit in Clostridium kluyveri, which showed specific-
ity towards butyrate, but neither valerate nor propanoate. However,
multiple citation searches using the original Madanet al. paper
yields no further effort to characterise this enzyme in humans,
meaning it has likely been superseded by SCHAD as described
Uptake and Metabolism of the Short-chain Fatty Acid Butyrate Current Drug Metabolism, 2012, Vol. 13, No. ?? 5
iv. Metabolism – other Routes
The ?-oxidative pathway accounts for much of the butyrate
taken up by the colonocyte – it is the primary fuel source for these
cells . However there must also be other intracellular effects if
butyrate is to act as an HDAC inhibitor, so it is reasonable to as-
sume that movement of butyrate into the ?-oxidative pathway is
regulated in order to allow movement into the nucleus. Studies in
human colorectal carcinoma (HT-29 Glc-/+) cells allude to this, with
?-oxidation acting as a regulator of the intracellular concentration
of butyrate (after conversion to any of the intermediates mentioned
above, butyrate cannot exit the mitochondria) . This is further
confirmed by comparing the oxidation rates with different concen-
trations of butyrate: 0.5mM results in 74% of the maximum oxida-
tion rate achieved with 2.0mM, suggesting that ?-oxidation of bu-
tyrate is limited past a certain threshold . Comparisons between
acetoacetate and 3-hydroxybutyrate produced by colonocytes in a
rat model suggest that some of the excess butyrate is diverted to-
wards the production of ketone bodies . However, this is dis-
puted in the literature, with studies on isolated colonocytes showing
increased acetoacetate production with increased butyrate concen-
trations (indicating increased ?-oxidation) [63,67].
Although aspects of the uptake and metabolism of butyrate
have been fairly well characterised in the literature, there are still
gaps in which assumptions, or the reliance on dated or conflicted
studies are used in place of more solid evidence. Particularly with
regard to the movement of butyrate once it has entered the cell there
is limited information on how butyrate may be managed or deliv-
ered to the ?-oxidation pathway. The availability and specificity, let
alone expression profiles of enzymes managing SCFA ?-oxidation
flux, and the levels at which control of that flux occur, remain un-
clear. Empirical data reviewed in  suggest LCFA metabolic
control occurs at the level of entry of acyl-coA to the mitochondria,
however the degree to which this level of control is exerted on
MCFA metabolism, or where control might be exerted is not clear.
It does appear from the data reviewed that butyrate metabolism is
saturable at levels below those which occur in the human gut .
The fate of excess butyrate in such a system is particularly unclear.
Likewise at system level the ?-oxidation metabolic pathway for
SCFA/MCFA will also be provided with substrate from LCFA
metabolism, and the metabolic environment of the tissue and host
will, to a degree, be influenced by the diet of the host. The possible
upregulation of monocarboxylate transporters as a mechanism for
managing excess lactate in glycolytic neoplasia further complicates
speculation on how butyrate metabolism may be affected specifi-
cally in those neoplastic tissues against which is may be used.
There is an urgent need to improve knowledge of the metabo-
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metabolic/dietary approaches to improve therapeutic outcome from
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Received: ????? 15, 2010
Revised: ????? 28, 2011 Accepted: ?????? 29, 2011