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Phytanic acid and pristanic acid, branched-chain fatty acids associated with Refsum disease and other inherited peroxisomal disorders, mediate intracellular Ca2+ signaling through activation of free fatty acid receptor GPR40.
[zellweger syndrome]
The
accumulation
of
the
two
branched-chain
fatty
acids
phytanic
acid
and
pristanic
acid
is
known
to
play
an
important
role
in
several
diseases
with
peroxisomal
impairment
,
like
Refsum
disease
,
Zellweger
syndrome
and
α-methylacyl-
CoA
racemase
deficiency
.
Recent
studies
elucidated
that
the
toxic
activity
of
phytanic
acid
and
pristanic
acid
is
mediated
by
multiple
mitochondrial
dysfunctions
,
generation
of
reactive
oxygen
species
and
Ca
2
+
deregulation
via
the
InsP
3
-
Ca
2
+
signaling
pathway
in
glial
cells
.
However
,
the
exact
signaling
mechanism
through
which
both
fatty
acids
mediate
toxicity
is
still
under
debate
.
Here
,
we
studied
the
ability
of
phytanic
acid
and
pristanic
acid
to
activate
the
free
fatty
acid
receptor
GPR
4
0
,
a
G-
protein-coupled
receptor
,
which
was
described
to
be
involved
in
the
Ca
2
+
signaling
of
fatty
acids
.
We
treated
HEK
293
cells
expressing
the
GPR
4
0
receptor
with
phytanic
acid
or
pristanic
acid
.
This
resulted
in
a
significant
increase
in
the
intracellular
Ca
2
+
level
,
similar
to
the
effect
seen
after
treatment
with
the
synthetic
GPR
4
0
agonist
GW
9508
.
Furthermore
,
we
demonstrate
that
the
GPR
4
0
activation
might
be
due
to
an
interaction
of
the
carboxylate
moiety
of
fatty
acids
with
the
receptor
.
Our
findings
indicate
that
the
phytanic
acid-
and
pristanic
acid-mediated
Ca
2
+
deregulation
can
involve
the
activation
of
GPR
4
0
.
Therefore
,
we
suppose
that
activation
of
GPR
4
0
might
be
part
of
the
signaling
cascade
of
the
toxicity
of
phytanic
and
pristanic
acids
.
Diseases
Validation
Diseases presenting
"multiple mitochondrial dysfunctions"
symptom
zellweger syndrome
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