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Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1.
[benign recurrent intrahepatic cholestasis]
Functional
defects
in
ATPase
class
I
type
8
B
membrane
1
(
ATP
8
B
1
or
familial
intrahepatic
cholestasis
1
,
FIC
1
)
lead
to
cholestasis
by
mechanism
(
s
)
that
are
not
fully
understood
.
One
proposed
pathophysiology
involves
aberrant
signaling
to
the
bile
acid
sensor
,
the
farnesoid
X
receptor
(
FXR
)
,
via
protein
kinase
C
ζ
(
PKC
ζ
)
.
The
following
cell
line-based
studies
investigated
whether
phospholipase
D
2
may
transduce
a
signal
from
FIC
1
to
FXR
.
PLD
2
gain
of
function
led
to
activation
of
the
bile
salt
export
pump
(
BSEP
)
promoter
,
a
well-characterized
FXR
response
.
BSEP
activation
by
PLD
2
could
be
blocked
by
abrogating
either
PKC
ζ
or
FXR
signaling
.
PLD
2
loss
of
function
led
to
a
reduction
in
BSEP
promoter
activity
.
In
addition
,
a
variety
of
proteins
that
are
activated
by
FXR
,
including
BSEP
,
were
reduced
in
HepG
2
cells
treated
with
PLD
2
siRNA
.
Similar
effects
were
observed
in
freshly
isolated
human
hepatocytes
.
Activation
of
BSEP
by
FIC
1
gain
of
function
was
blocked
when
PLD
2
but
not
PLD
1
was
silenced
.
Overexpression
of
wild-
type
but
not
Byler
mutant
FIC
1
led
to
an
increase
in
membrane
associated
PLD
activity
.
An
intermediate
level
of
activation
of
PLD
activity
was
induced
when
a
benign
recurrent
intrahepatic
cholestasis
FIC
1
mutant
construct
was
expressed
.
These
studies
show
that
FIC
1
signals
to
FXR
via
a
signaling
pathway
including
PLD
2
and
PKC
ζ
.