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Endogenous β-glucocerebrosidase activity in Abca12⁻/⁻epidermis elevates ceramide levels after topical lipid application but does not restore barrier function.
[harlequin ichthyosis]
ABCA
12
mutations
disrupt
the
skin
barrier
and
cause
harlequin
ichthyosis
.
We
previously
showed
Abca
12
(
-
/
-
)
skin
has
increased
glucosylceramide
(
GlcCer
)
and
correspondingly
lower
amounts
of
ceramide
(
Cer
)
.
To
examine
why
loss
of
ABCA
12
leads
to
accumulation
of
GlcCer
,
de
novo
sphingolipid
synthesis
was
assayed
using
[
(
14
)
C
]
serine
labeling
in
ex
vivo
skin
cultures
.
A
defect
was
found
in
β-glucocerebrosidase
(
GCase
)
processing
of
newly
synthesized
GlcCer
species
.
This
was
not
due
to
a
decline
in
GCase
function
.
Abca
12
(
-
/
-
)
epidermis
had
5
-
fold
more
GCase
protein
(
n
=
4
,
P
<
0
.
01
)
,
and
a
5
-
fold
increase
in
GCase
activity
(
n
=
3
,
P
<
0
.
05
)
.
As
with
Abca
12
(
+
/
+
)
epidermis
,
immunostaining
in
null
skin
showed
a
typical
interstitial
distribution
of
the
GCase
protein
in
the
Abca
12
(
-
/
-
)
stratum
corneum
.
Hence
,
we
tested
whether
the
block
in
GlcCer
conversion
could
be
circumvented
by
topically
providing
GlcCer
.
This
approach
restored
up
to
15
%
of
the
lost
Cer
products
of
GCase
activity
in
the
Abca
12
(
-
/
-
)
epidermis
.
However
,
this
level
of
barrier
ceramide
replacement
did
not
significantly
reduce
trans-epidermal
water
loss
function
.
Our
results
indicate
loss
of
ABCA
12
function
results
in
a
failure
of
precursor
GlcCer
substrate
to
productively
interact
with
an
intact
GCase
enzyme
,
and
they
support
a
model
of
ABCA
12
function
that
is
critical
for
transporting
GlcCer
into
lamellar
bodies
.
