Biomedical Engineering Reference
In-Depth Information
In contrast to MCT1, MCT2-4 are known to play a much more tissue-specific
role in the transport of monocarboxylates. Analysis of MCT2 mRNA and protein
expression in a variety of species has shown that major species-specific variations
in tissue distribution exist. MCT2 expression in rodents is evident in a variety of
tissues, including brain, liver, kidney, and testes.
14
Although the major MCT present
in rodent neurons is MCT2, its expression in human brain appears to be minimal.
Both expressed sequence tag (EST) expression and Northern blot analysis of human
brain has found only very low or trace expression of MCT2.
15
However, lactate uptake
by neurons has been suggested, with some controversy, as a major source of energy
substrates for neuronal activation.
16
,
17
Therefore, if a high-affinity lactate transporter
is required by adult human neurons, its identity and characteristics are yet to be
determined.
MCT3 is unique among MCTs in that it is reportedly expressed in the retinal
pigment epithelium (RPE), although the human EST database (Unigene) suggests a
somewhat broader expression profile (National Center for Biotechnology Informa-
tion). MCT3 is located at the basolateral membrane, where it functions in tandem
with MCT1 on the apical side.
18
The presence of the lower-affinity MCT3 (
K
m
∼
5.8 mM versus
K
m
∼
3.5 mM) in the basolateral membrane of the RPE cell creates a
more effective mechanism for lactate efflux out of the retina and into the bloodstream.
MCT4 works synergistically with MCT1 and is limited in its tissue expression. In
humans MCT4 expression is limited to highly glycolytic tissues and has been detected
in skeletal muscle, heart, and liver.
19
In human skeletal muscle MCT4 expression is
highly variable among individuals and is localized primarily to type II glycolytic
muscle fibers, while MCT1 expression varies little between individuals and is present
in both type I and type II muscle fibers.
20
This coexpression of MCT1 with other MCTs
probably results from the unique physical and biochemical properties associated with
each MCT family member.
19
For example, the
K
m
of MCT1 for lactate is about 3.5
mM,
21
17 to 34 mM).
22
Because
the concentration of lactate in the blood is normally about 1.5 mM, this extreme
difference in substrate affinity results in MCT4 acting more like an assistant to MCT1
to further enhance lactate efflux from glycolytic muscle fibers.
19
In the human colon, there exist symbiotic bacteria that breakdown undigested
carbohydrates to produce significant amounts of short-chain fatty acids (SCFAs)
such as butyrate, propionate, and acetate. These SCFAs serve as major precursors in
generating glucose, amino acids, and ketone bodies.
23
SCFAs also provide a major
fuel source for the colonocytes, with butyrate being the most preferred substrate
for oxidation.
24
The colonocytes that line the lumen of the human colon exhibit
polarized expression of MCTs, where MCT1 is expressed on the apical surface and
MCT4 is localized to the basolateral surface.
25
These transporters are critical for
proper maintenance of the colon epithelium because SCFAs such as butyrate in the
colon have been shown to regulate many essential cellular functions, including cell
growth, proliferation, and differentiation.
26
The presence of MCT1 on the apical
side and the low-affinity MCT4 on the basolateral surface of the colon epithelium
provides a means by which SCFAs can be concentrated in the colonic epithelial cell
for catabolism and regulatory processes. Additionally, the polarized expression of
while that of MCT4 is significantly higher (
K
m
∼
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