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Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
caused
by
mutations
in
the
ABCD
1
gene
encoding
ALDP
,
an
ATP-binding-cassette
(
ABC
)
transporter
located
in
the
peroxisomal
membrane
.
ALDP
deficiency
results
in
impaired
peroxisomal
β-oxidation
and
the
subsequent
accumulation
of
very
long
-chain
fatty
acids
(
VLCFA
;
>
C
2
2
:
0
)
in
plasma
and
tissues
.
VLCFA
are
primarily
derived
from
endogenous
synthesis
by
ELOVL
1
.
Therefore
inhibiting
this
enzyme
might
constitute
a
feasible
therapeutic
approach
.
In
this
paper
we
demonstrate
that
bezafibrate
,
a
PPAR
pan
agonist
used
for
the
treatment
of
patients
with
hyperlipidaemia
reduces
VLCFA
levels
in
X-
ALD
fibroblasts
.
Surprisingly
,
the
VLCFA-lowering
effect
was
independent
of
PPAR
activation
and
not
caused
by
the
increase
in
either
mitochondrial
or
peroxisomal
fatty
acid
β-oxidation
capacity
.
In
fact
,
our
results
show
that
bezafibrate
reduces
VLCFA
synthesis
by
decreasing
the
synthesis
of
C
2
6
:
0
through
a
direct
inhibition
of
fatty
acid
elongation
activity
.
Taken
together
,
our
data
indicate
bezafibrate
as
a
potential
pharmacotherapeutic
treatment
for
X-
ALD
.
A
clinical
trial
is
currently
ongoing
to
evaluate
the
effect
in
patients
with
X-
ALD
.
Diseases
Validation
Diseases presenting
"impaired peroxisomal"
symptom
adrenomyeloneuropathy
neonatal adrenoleukodystrophy
x-linked adrenoleukodystrophy
zellweger syndrome
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