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Lipid rafts are essential for peroxisome biogenesis in HepG2 cells.
[zellweger syndrome]
Peroxisomes
are
particularly
abundant
in
the
liver
and
are
involved
in
bile
salt
synthesis
and
fatty
acid
metabolism
.
Peroxisomal
membrane
proteins
(
PMPs
)
are
required
for
peroxisome
biogenesis
[
e
.
g
.
,
the
interacting
peroxisomal
biogenesis
factors
Pex
13
p
and
Pex
14
p
]
and
its
metabolic
function
[
e
.
g
.
,
the
adenosine
triphosphate-binding
cassette
transporters
adrenoleukodystrophy
protein
(
ALDP
)
and
PMP
70
]
.
Impaired
function
of
PMPs
is
the
underlying
cause
of
Zellweger
syndrome
and
X-
linked
adrenoleukodystrophy
.
Here
we
studied
for
the
first
time
the
putative
association
of
PMPs
with
cholesterol-enriched
lipid
rafts
and
their
function
in
peroxisome
biogenesis
.
Lipid
rafts
were
isolated
from
Triton
X-
100
-
lysed
or
Lubrol
WX-lysed
HepG
2
cells
and
analyzed
for
the
presence
of
various
PMPs
by
western
blotting
.
Lovastatin
and
methyl-
beta
-cyclodextrin
were
used
to
deplete
cholesterol
and
disrupt
lipid
rafts
in
HepG
2
cells
,
and
this
was
followed
by
immunofluorescence
microscopy
to
determine
the
subcellular
location
of
catalase
and
PMPs
.
Cycloheximide
was
used
to
inhibit
protein
synthesis
.
Green
fluorescent
protein-tagged
fragments
of
PMP
70
and
ALDP
were
analyzed
for
their
lipid
raft
association
.
PMP
70
and
Pex
14
p
were
associated
with
Triton
X-
100
-
resistant
rafts
,
ALDP
was
associated
with
Lubrol
WX-resistant
rafts
,
and
Pex
13
p
was
not
lipid
raft-associated
in
HepG
2
cells
.
The
minimal
peroxisomal
targeting
signals
in
ALDP
and
PMP
70
were
not
sufficient
for
lipid
raft
association
.
Cholesterol
depletion
led
to
dissociation
of
PMPs
from
lipid
rafts
and
impaired
sorting
of
newly
synthesized
catalase
and
ALDP
but
not
Pex
14
p
and
PMP
70
.
Repletion
of
cholesterol
to
these
cells
efficiently
reestablished
the
peroxisomal
sorting
of
catalase
but
not
ALDP
.
Human
PMPs
are
differentially
associated
with
lipid
rafts
independently
of
the
protein
homology
and
/
or
their
functional
interaction
.
Cholesterol
is
required
for
peroxisomal
lipid
raft
assembly
and
peroxisome
biogenesis
.