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Ceramide stimulates ABCA12 expression via peroxisome proliferator-activated receptor {delta} in human keratinocytes.
[harlequin ichthyosis]
ABCA
12
(
ATP
binding
cassette
transporter
,
family
12
)
is
a
cellular
membrane
transporter
that
facilitates
the
delivery
of
glucosylceramides
to
epidermal
lamellar
bodies
in
keratinocytes
,
a
process
that
is
critical
for
permeability
barrier
formation
.
Following
secretion
of
lamellar
bodies
into
the
stratum
corneum
,
glucosylceramides
are
metabolized
to
ceramides
,
which
comprise
approximately
50
%
of
the
lipid
in
stratum
corneum
.
Gene
mutations
of
ABCA
12
underlie
harlequin
ichthyosis
,
a
devastating
skin
disorder
characterized
by
abnormal
lamellar
bodies
and
a
severe
barrier
abnormality
.
Recently
we
reported
that
peroxisome
proliferator-activated
receptor
(
PPAR
)
and
liver
X
receptor
activators
increase
ABCA
12
expression
in
human
keratinocytes
.
Here
we
demonstrate
that
ceramide
(
C
(
2
)
-
Cer
and
C
(
6
)
-
Cer
)
,
but
not
C
(
8
)
-
glucosylceramides
,
sphingosine
,
or
ceramide
1
-
phosphate
,
increases
ABCA
12
mRNA
expression
in
a
dose-
and
time-dependent
manner
.
Inhibitors
of
glucosylceramide
synthase
,
sphingomyelin
synthase
,
and
ceramidase
and
small
interfering
RNA
knockdown
of
human
alkaline
ceramidase
,
which
all
increase
endogenous
ceramide
levels
,
also
increased
ABCA
12
mRNA
levels
.
Moreover
,
simultaneous
treatment
with
C
(
6
)
-
Cer
and
each
of
these
same
inhibitors
additively
increased
ABCA
12
expression
,
indicating
that
ceramide
is
an
important
inducer
of
ABCA
12
expression
and
that
the
conversion
of
ceramide
to
other
sphingolipids
or
metabolites
is
not
required
.
Finally
,
both
exogenous
and
endogenous
ceramides
preferentially
stimulate
PPARdelta
expression
(
but
not
other
PPARs
or
liver
X
receptors
)
,
whereas
PPARdelta
knockdown
by
siRNA
transfection
specifically
diminished
the
ceramide-induced
increase
in
ABCA
12
mRNA
levels
,
indicating
that
PPARdelta
is
a
mediator
of
the
ceramide
effect
.
Together
,
these
results
show
that
ceramide
,
an
important
lipid
component
of
epidermis
,
up-regulates
ABCA
12
expression
via
the
PPARdelta-mediated
signaling
pathway
,
providing
a
substrate-driven
,
feed-forward
mechanism
for
regulating
this
key
lipid
transporter
.
Diseases
Validation
Diseases presenting
"a devastating skin disorder characterized by abnormal lamellar bodies and a severe barrier abnormality"
symptom
harlequin ichthyosis
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