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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
"ichthyosis"
symptom
child syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
harlequin ichthyosis
hirschsprung disease
junctional epidermolysis bullosa
kallmann syndrome
lamellar ichthyosis
This symptom has already been validated