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MCT1 gene expression; however, the details of this mechanism are unknown. It has
been shown that suckling rat pups, where the diet is composed primarily of fats
from the mother's milk, have increased levels of MCT1 protein in brain endothelial
cells compared to adult rats.
29
Additionally, adult rats fed a high-fat diet, which re-
sults in high levels of plasma ketones, have increased expression of MCT1 at the
blood-brain barrier.
30
Furthermore, butyrate greatly enhances MCT1 transcript and
protein expression in a human intestinal cell line.
31
Exercise training in humans also
dramatically affects MCT expression in skeletal muscle. During periods of intense
muscle activity in humans, lactate production by glycolytic muscle cells is greatly
enhanced. MCT1 in the plasma membrane reportedly increases by as much as 76%,
while MCT4 protein content increased by 34% after 8 weeks of exercise training.
20
Additionally, in the heart, where lactate is a major fuel source for oxidative phosphory-
lation, up-regulation of MCTs is even more dramatic following periods of moderate-
and high-intensity exercise.
19
Although it is clear from these results that high levels of
lactate and circulating ketone bodies can induce MCT1 gene transcription, the exact
pathway that is involved remains elusive.
Some clues as to the mechanism of MCT1 transcriptional regulation are emerging.
With the recent release of the human genome sequence and characterization of the
human MCT1 promoter, researchers have been able to identify several transcription
factor-binding sites within the promoter region. These conserved sequences within
the human MCT1 promoter include binding sites for upstream stimulatory factors
(USFs), nuclear factor-
B), stimulating protein 1 (SP1), activator protein
1 (AP1), and activator protein 2 (AP2).
32
Of these putative MCT1 transcriptional
regulators, only USFI and USFII have been shown in vitro to regulate MCT1 gene
expression. Overexpression of USFI and USFII in a human intestinal cell line (Caco-2)
led to a 34% and 84% decrease in MCT1 promoter activity, respectively.
33
In another
study, CoCl
2
, an oxidative phosphorylation inhibitor and putative activator of the
transcription factor HIF-1
B (NF
, caused an increase in MCT1 mRNA in cultured rat brain
endothelial cells (RBE4).
4
Additionally, in a more recent study it was hypothesized
that increased MCT1 mRNA expression in brain may be mediated by HIF1
α
α
in a
spontaneous hypertensive rat model after an ischemic insult.
34
In contrast to these
reports, a recent analysis of the human MCT1 and MCT4 promoters indicated that only
MCT4 is responsive to hypoxia through a direct interaction with HIF1
.
35
Although
the MCT1 promoters of different species contain many of the same transcription
factor-binding sites, the sequences vary greatly. Therefore, it is possible that some
transcriptional regulator elements among species are conserved, whereas others, such
as response to hypoxia, are not.
Evidence supporting hormonal regulation of MCT1 transcription has also been
reported. In a thyroid cell line (FRTL-5) MCT1 transcription was found to be regulated
by thyroid-stimulating hormone (TSH) through cAMP-dependent pathways.
36
In a
human intestinal cell line (Caco-2), addition of leptin to the apical surface leads to
a small but significant increase in MCT1 protein in the apical membrane.
37
This
increase in MCT1 expression induced by leptin was attributed to increased MCT1
mRNA production and enhanced translocation of the transporter protein to the plasma
membrane from intracellular pools.
37
α
Further studies with Caco-2 cells have shown
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