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Histone deacetylase inhibitor upregulates peroxisomal fatty acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells.
[x-linked adrenoleukodystrophy]
In
X-
ALD
,
mutation
/
deletion
of
ALD
gene
(
ABCD
1
)
and
the
resultant
very
long
chain
fatty
acid
(
VLCFA
)
derangement
has
dramatically
opposing
effects
in
astrocytes
and
oligodendrocytes
.
While
loss
of
Abcd
1
in
astrocytes
produces
a
robust
inflammatory
response
,
the
oligodendrocytes
undergo
cell
death
leading
to
demyelination
in
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
.
The
mechanisms
of
these
distinct
pathways
in
the
two
cell
types
are
not
well
understood
.
Here
,
we
investigated
the
effects
of
Abcd
1
-
knockdown
and
the
subsequent
alteration
in
VLCFA
metabolism
in
human
U
87
astrocytes
and
rat
B
12
oligodendrocytes
.
Loss
of
Abcd
1
inhibited
peroxisomal
β-oxidation
activity
and
increased
expression
of
VLCFA
synthesizing
enzymes
,
elongase
of
very
long
chain
fatty
acids
(
ELOVLs
)
(
1
and
3
)
in
both
cell
types
.
However
,
higher
induction
of
ELOVL
's
in
Abcd
1
-
deficient
B
12
oligodendrocytes
than
astrocytes
suggests
that
ELOVL
pathway
may
play
a
prominent
role
in
oligodendrocytes
in
X-
ALD
.
While
astrocytes
are
able
to
maintain
the
cellular
homeostasis
of
anti-apoptotic
proteins
,
Abcd
1
-
deletion
in
B
12
oligodendrocytes
downregulated
the
anti-apototic
(
Bcl-
2
and
Bcl-x
L
)
and
cell
survival
(
phospho-
Erk
1
/
2
)
proteins
,
and
upregulated
the
pro-apoptotic
proteins
(
Bad
,
Bim
,
Bax
and
Bid
)
leading
to
cell
loss
.
These
observations
provide
insights
into
different
cellular
signaling
mechanisms
in
response
to
Abcd
1
-
deletion
in
two
different
cell
types
of
CNS
.
The
apoptotic
responses
were
accompanied
by
activation
of
caspase-
3
and
caspase-
9
suggesting
the
involvement
of
mitochondrial
-caspase-
9
-
dependent
mechanism
in
Abcd
1
-
deficient
oligodendrocytes
.
Treatment
with
histone
deacetylase
(
HDAC
)
inhibitor
suberoylanilide
hydroxamic
acid
(
SAHA
)
corrected
the
VLCFA
derangement
both
in
vitro
and
in
vivo
,
and
inhibited
the
oligodendrocytes
loss
.
These
observations
provide
a
proof-of
principle
that
HDAC
inhibitor
SAHA
may
have
a
therapeutic
potential
for
X-
ALD
.
Diseases
Validation
Diseases presenting
"very long chain fatty acid"
symptom
adrenomyeloneuropathy
neonatal adrenoleukodystrophy
x-linked adrenoleukodystrophy
zellweger syndrome
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