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Cholesterol biosynthesis and ER stress in peroxisome deficiency.
[zellweger syndrome]
Cholesterol
biosynthesis
is
a
multi-step
process
involving
more
than
20
enzymes
in
several
subcellular
compartments
.
The
pre-squalene
segment
of
the
cholesterol
/
isoprenoid
biosynthetic
pathway
is
localized
in
peroxisomes
.
This
review
intends
to
highlight
recent
findings
illustrating
the
important
role
peroxisomes
play
in
cholesterol
biosynthesis
and
maintenance
of
cholesterol
homeostasis
.
Disruption
of
the
Pex
2
gene
leads
to
peroxisome
deficiency
and
widespread
metabolic
dysfunction
.
The
Pex
2
(
-
/
-
)
mouse
model
for
Zellweger
syndrome
enabled
us
to
evaluate
the
role
of
peroxisomes
in
cholesterol
biosynthesis
.
These
studies
have
shown
that
Pex
2
(
-
/
-
)
mice
exhibit
low
levels
of
cholesterol
in
plasma
and
liver
.
Pex
2
(
-
/
-
)
mice
were
unable
to
maintain
normal
cholesterol
homeostasis
despite
activation
of
SREBP-
2
,
the
master
transcriptional
regulator
of
cholesterol
biosynthesis
,
and
increased
protein
levels
and
activities
of
cholesterol
biosynthetic
enzymes
.
The
SREBP-
2
pathway
remained
activated
even
after
normalization
of
hepatic
cholesterol
levels
in
response
to
bile
acid
feeding
as
well
as
in
extrahepatic
tissues
and
the
liver
of
neonatal
and
longer
surviving
Pex
2
mutants
,
where
cholesterol
levels
were
normal
.
Several
studies
have
shown
that
endoplasmic
reticulum
(
ER
)
stress
can
dysregulate
lipid
metabolism
via
SREBP
activation
independently
of
intracellular
cholesterol
concentration
.
We
demonstrated
that
peroxisome
deficiency
activates
endoplasmic
reticulum
stress
pathways
in
Pex
2
(
-
/
-
)
mice
,
especially
the
integrated
stress
response
mediated
by
PERK
and
ATF
4
signaling
,
and
thereby
leads
to
dysregulation
of
the
SREBP-
2
pathway
.
Our
findings
suggest
that
functional
peroxisomes
are
necessary
to
prevent
chronic
ER
stress
and
dysregulation
of
the
endogenous
sterol
response
pathway
.
The
constitutive
activation
of
ER
stress
pathways
might
contribute
to
organ
pathology
and
metabolic
dysfunction
in
peroxisomal
disorder
patients
.