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Straight-chain acyl-CoA oxidase knockout mouse accumulates extremely long chain fatty acids from alpha-linolenic acid: evidence for runaway carousel-type enzyme kinetics in peroxisomal beta-oxidation diseases.
[neonatal adrenoleukodystrophy]
Extremely
long
chain
polyunsaturated
fatty
acids
(
ELCPs
)
with
>
24
carbons
and
four
or
more
double
bonds
are
normally
found
in
excitatory
tissues
but
have
no
known
function
,
and
are
greatly
increased
in
brain
and
other
tissues
of
humans
with
peroxisomal
disorders
.
Straight-chain
acyl-
CoA
oxidase
(
AOX
)
catalyzes
the
first
,
rate-limiting
step
of
peroxisomal
beta
-oxidation
of
very
-
long
-chain
saturated
and
unsaturated
fatty
acids
.
We
have
studied
the
polyunsaturated
fatty
acid
metabolism
of
AOX
knockout
mice
(
AOX-
/
-
as
a
model
of
human
AOX
deficiency
(
pseudo-
neonatal
adrenoleukodystrophy
)
,
and
as
a
genetic
tool
to
test
the
putative
peroxisomal
beta
-oxidation
involvement
in
polyunsaturated
fatty
acid
synthesis
.
Liver
lipids
of
26
-
day
-old
weanling
AOX-
/
-
mice
livers
accumulate
n-
3
and
n-
6
ELCPs
from
C
2
4
to
C
3
0
with
5
and
6
double
bonds
,
have
356
+
/
-
66
microg
/
g
docosahexaenoic
acid
(
22
:
6
n-
3
)
,
similar
to
congenic
(
AOX
-
/
*
=
AOX
+
/
+
and
AOX
+
/
-
)
controls
(
401
+
/
-
96
microg
/
g
)
,
but
increased
22
:
5
n-
6
(
22
.
4
+
/
-
3
.
7
vs
6
.
4
+
/
-
1
.
5
microg
/
g
)
.
AOX
+
/
*
mice
injected
intraperitoneally
at
23
days
with
[
U-
(
13
)
C
]
-
18
:
3
n-
3
show
strong
labeling
of
22
:
6
n-
3
after
72
h
,
whereas
AOX
-
/
-
mice
display
less
labeling
of
22
:
6
n-
3
but
strong
tracer
incorporation
into
24
:
6
n-
3
,
26
:
6
n-
3
,
and
28
:
6
n-
3
,
after
the
same
period
.
These
data
suggest
that
ELCPs
are
natural
runaway
elongation
by
-products
of
22
:
6
n-
3
and
22
:
5
n-
6
synthesis
,
which
are
normally
disposed
of
by
peroxisomal
beta
-oxidation
.
Under
conditions
with
impaired
peroxisomal
beta
-oxidation
,
such
as
Zellweger
syndrome
and
adrenoleukodystrophies
,
ELCPs
accumulate
due
to
increased
synthesis
and
impaired
disposal
.
Two
mechanisms
for
the
formation
of
these
runaway
elongation
by
-products
and
the
involvement
of
secondary
carnitine
deficiency
in
this
process
are
proposed
:
n-
3
ELCPs
are
synthesized
by
a
carnitine-dependent
multifunctional
mitochondrial
docosahexaenoic
acid
synthase
(
mtDHAS
)
which
normally
synthesizes
primarily
22
:
6
n-
3
,
while
n-
6
ELCPs
are
synthesized
by
independent
elongation
enzymes
in
the
endoplasmic
reticulum
.
Diseases
Validation
Diseases presenting
"liver lipids"
symptom
neonatal adrenoleukodystrophy
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