Tài liệu Báo cáo khoa học: SREBPs: SREBP function in glia–neuron interactions pdf

MINIREVIEW
SREBPs: SREBP function in glia–neuron interactions
Nutabi Camargo, August B. Smit and Mark H. G. Verheijen
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam,
VU University Amsterdam, The Netherlands
Introduction
The sterol regulatory element-binding proteins
(SREBPs) belong to the family of basic helix–loop–
helix leucine zipper transcription factors, which are
known to regulate lipid metabolism in liver and
adipose tissue. The SREBP family consists of SREBP-
1a, SREBP-1c and SREBP-2 [1]. SREBP-1c and
SREBP-2 preferentially govern the upregulation of
genes involved in fatty acid and cholesterol metabo-
lism, respectively, whereas SREBP-1a activates both
pathways [1,2]. SREBP-1a is expressed ubiquitously at
low levels, in contrast to the differentially regulated
expression of SREBP-1c and SREBP-2. Expression of
SREBP-2 is induced under conditions of sterol deple-
tion, whereas SREBP-1c expression is under the
control of insulin, glucose and fatty acids in several
cells types, among which are Schwann cells [1–3]. A
characteristic of the SREBP transcription factors is
their post-translational activation by SREBP cleavage-
activating protein (SCAP), which is under the control
of lipid levels. SCAP acts as a sterol sensor that, in
sterol-depleted cells, escorts the SREBPs from the
endoplasmic reticulum to the Golgi, where they are
activated via processing by two membrane-associated
proteases, site 1 protease and site 2 protease. The
mature and transcriptionally active forms of the

SREBPs translocate to the nucleus, where they bind
Keywords
astrocyte; cholesterol; fatty acid; glia; lipid
metabolism; myelin; neuron; Schwann cell;
SREBP; synapse
Correspondence
M. H. G. Verheijen, Department of
Molecular and Cellular Neurobiology, Center
for Neurogenomics and Cognitive Research,
VU University Amsterdam, Neuroscience
Campus Amsterdam, De Boelelaan 1085,
1081 HV Amsterdam, The Netherlands
Fax: +31 20 598 9281
Tel: +31 20 598 7120
E-mail:
(Received 28 August 2008, accepted 10
October 2008)
doi:10.1111/j.1742-4658.2008.06808.x
The mammalian nervous system is relatively autonomous in lipid
metabolism. In particular, Schwann cells in the peripheral nervous system,
and oligodendrocytes and astrocytes in the central nervous system, are
highly active in lipid synthesis. Previously, enzymatic lipid synthesis in the
liver has been demonstrated to be under the control of the sterol regulatory
element-binding protein (SREBP) transcription factors. Here, we put for-
ward the view that SREBP transcription factors in glia cells control the
synthesis of lipids involved in various glia–neuron interactions, thereby
affecting a range of neuronal functions. This minireview compiles current
knowledge on the involvement of Schwann cell SREBPs in myelination of
axons in the peripheral nervous system, and proposes a role for astrocyte
SREBPs in neuronal functioning in the central nervous system.

Abbreviations
ApoE, apolipoprotein E; CNS, central nervous system; D5D, delta-5 desaturase; D6D, delta-6 desaturase; DPN, diabetic peripheral
neuropathy; EFA, essential fatty acid; MUFA, monounsaturated fatty acid; PNS, peripheral nervous system; PUFA, polyunsaturated fatty
acid; SCAP, sterol regulatory element-binding protein cleavage-activating protein; SCD1, stearoyl-CoA desaturase 1; SCD2, stearoyl-CoA
desaturase 2; SREBP, sterol regulatory element-binding protein.
628 FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS
gene promoters containing sterol regulatory elements.
These SREBP target genes are involved in the synthe-
sis and metabolism of cholesterol and fatty acids [1,2].
The central nervous system (CNS) and peripheral
nervous system (PNS) need to be highly active in lipid
synthesis, as both are shielded from lipids in the circu-
lation by, respectively, the blood–brain barrier and the
blood–nerve barrier [4–6]. Therefore, the nervous
system may be viewed as being largely autonomous in
lipid metabolism. This raises the issue of the identity
of the cell type(s) and molecular processes involved in
lipid synthesis in the PNS and CNS. Although the
ratio of neurons to glial cells in the vertebrate nervous
system is approximately 1 : 10, research aimed at
understanding nervous system functions has only
recently started to acknowledge the full contribution of
glial function. Glia cells were long viewed as support-
ing neuronal functions in development, metabolism
and insulation, but were recently identified as active
partners in the modulation of synaptic transmission
[7]. The functionally diverse glia–neuron interactions
include both contact-dependent and soluble factors,
and involve a wide spectrum of molecules, among
which are lipids. Also, the role of lipids in the patho-

physiology of several neurological diseases has recently
been demonstrated. Whereas SREBPs were known to
be involved in diseases associated with dysfunction of
lipid metabolism in several organs, e.g. liver, kidney
and pancreas [1,2,8], the view has started to emerge
that glia SREBPs are also involved in neurological dis-
eases. Here, we discuss the current understanding of
the role of SREBPs in glia–neuron interactions in
health and disease.
Role of Schwann cell SREBPs in
myelination
The rapid saltatory conduction of neural action poten-
tials is crucially dependent on the compact insulating
myelin layers around axons. The myelin membrane is
an organelle synthesized by Schwann cells in the PNS,
and by oligodendrocytes in the CNS. The electrical
insulating property of the myelin membrane is pro-
vided by its high and characteristic lipid content.
Although it has been suggested that many of these
myelin lipids are synthesized in the nerve itself, as was
demonstrated for cholesterol [4,5], the factors regulat-
ing their synthesis have been largely unknown. Our
recently reported expression profiling of the peripheral
nerve during myelination has provided many insights
into this, and points to a central role for SREBPs [9].
The biochemical characteristic that distinguishes
myelin from other plasma membranes is its exception-
ally high lipid ⁄ protein ratio. The myelin membrane
contains myelin-specific proteins, such as myelin pro-
tein zero, peripheral myelin protein-22, myelin asso-

ciated glycoprotein (MAG) and myelin basic protein,
but no myelin-specific lipids. Nevertheless, whereas all
major lipid classes are present in myelin, as in other
membranes, the myelin membrane is enriched in galac-
tosphingolipids, saturated long-chain fatty acids and
cholesterol, the last being the most abundant lipid (see
[10] for a comprehensive review on the molecular con-
stituents of PNS myelin).
SREBPs and myelin cholesterol synthesis
With the membrane surface area expanding spectacu-
larly by 6500-fold during myelination [11], it is of inter-
est that almost all of the cholesterol in the myelin
membrane is synthesized by the nerve itself [4]. In line
with this, myelination and remyelination is not affected
by deletion of the low-density lipoprotein receptor [12].
Studies on cholesterol biosynthesis in the myelin mem-
brane have shown that exposure of rats to a diet con-
taining tellurium, which blocks the conversion
catalyzed by squalene epoxidase, leads to an accumula-
tion of squalene and an absence of cholesterol in the
nerve [13]. This results in rapid PNS demyelination for
a week, after which remyelination occurs, even with
continuing tellurium exposure [14]. Together, these
studies show that glial cholesterol synthesis is crucial
for myelin membrane formation and integrity. Observa-
tions on the transcriptional control of the cholesterol
pathway are in line with this, as this process follows the
active period of myelination [9,15,16]. Importantly,
SREBP-2 follows the same time course of expression
[3,9,17]. Together with the demonstrated role for

SREBP-2 in cholesterol metabolism in other tissues,
this points to an important role for Schwann cell
SREBP-2 in the synthesis of myelin cholesterol (Fig. 1).
It should be noted that expression levels of SREBP-1a
in Schwann cells are continuously very low, whereas
SREBP-1c expression is strongly upregulated after mye-
lination in adults, as will be discussed below [3,9,18].
Interestingly, expression analysis of SREBPs in two
different mouse models for PNS dysmyelination, the
Trembler mouse [17] and the Krox-20 knockout mouse
[18], shows reduced expression of SREBP-2 but not of
SREBP-1a or SREBP-1c. Together with the observa-
tions that dysmyelination in these models is accompa-
nied by reduced myelin lipid synthesis [10,18], these
data support a major role for SREBP2 in myelin lipid
synthesis. It should be noted that ectopic expression of
Krox-20 in Schwann cells in vitro induces expression of
lipogenic genes [19]. Also, other in vitro studies suggest
N. Camargo et al. SREBP function in glia–neuron interactions
FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS 629
that, whereas Krox-20 does not induce the expression
of SREBP-2, it acts with SREBPs on the activation of
lipogenic gene promoters, such as 3-hydroxy-3-methyl-
glutaryl-CoA reductase (HMGcR) and stearoyl-CoA
desaturase 2 (SCD2) [18].
In summary, both expression analysis and molecular
approaches in vitro indicate a role for SREBP-2 in the
control of the cholesterol synthesis pathway during
myelination.
SREBPs and fatty acyl components of

myelin lipids
Myelin membrane lipids have a fatty acid composition
that is distinguishable from that of other membranes;
they have high levels of oleic acid [C18:1 (n – 9)],
which is the major myelin fatty acid, and of very long-
chain saturated fatty acids (> C18) [10]. Interestingly,
the ratio between C18:1 and C18:2 increases strongly
during myelination [20]. In line with these observa-
tions, SCD2, which may desaturase C18:0 into C18:1,
follows the same time course of expression as struc-
tural myelin protein genes [9,20,21]. The observations
that SREBP1 and SREBP2, as well as their target
genes encoding fatty acid synthase and SCD2, are up-
regulated in the developing peripheral nerve [3,9,21]
suggest an important role for SREBPs in determining
myelin fatty acid composition, and therefore fatty acyl
components for membrane phospholipids.
Unlike the expression of SREBP-2 and cholestero-
genic enzymes, which are downregulated after the
active myelination period, the expression of Schwann
cell SREBP-1c is strongly upregulated in the mature
nerve [3,9]. This suggests that the mature nerve is
highly active in fatty acid metabolism. In line with this
is our observation that adult peripheral nerves contain
high amounts of storage lipids in their epineurial com-
partment, and that local lipid metabolism is important
for normal nerve function [9]. This seems relevant for
a number of human diseases that produce peripheral
neuropathies and are associated with altered lipid
metabolism. Refsum’s disease is caused by defective

Schwann cell branched chain fatty acid oxidation, and
leads to a sensorimotor demyelinating neuropathy [22].
Also, mutation of Lpin1, a phosphatidic acid phospha-
tase that serves as a key enzyme in the biosynthetic
pathway of triglycerides and phospholipids, causes
lipodystrophy that includes the epineurial compart-
ment, and is associated with demyelinating peripheral
neuropathy [9]. Recent observations on a Schwann
cell-specific Lpin1 mutant mouse suggest that depletion
of Lpin1 function in Schwann cells only is sufficient to
induce a demyelinating phenotype [23]. Whether lipids
from the epineurial compartment are implicated in
functioning of axons and Schwann cells in the endo-
neurial compartment is an intriguing hypothesis that
remains to be evaluated.
Our observation that SREBP-1c is expressed in
Schwann cells of adult peripheral nerve, together with
observations of others that the action of SREBP-1c in
multiple tissues is affected in diabetes, suggest that
malfunction of SREBP-1c may underlie the patholo-
gical changes associated with diabetic peripheral
neuropathy (DPN) [3,24]. Type 1 diabetes mellitus is
thought to impair polyunsaturated fatty acid (PUFA)
metabolism by decreasing fatty acid desaturase activ-
ity, resulting in lower PUFA content in membrane
phospholipids of multiple tissues, including the periph-
eral nerve [25]. Dietary supply of PUFAs improved the
impaired nerve conduction velocity in a rodent type I
DPN and also in humans [25]. In line with these obser-
vations, PUFAs have been demonstrated to modify

the activity of axonal Na
+
⁄ K
+
-ATPases [26]. Interest-
ingly, SREBP-1c has been demonstrated to mediate
the insulin-induced transcription of stearoyl-CoA
desaturase (SCD1), delta-5 desaturase (D5D) and
delta-6 desaturase (D6D) [27]. Whereas SCD1 is
involved in the biosynthesis of monounsaturated fatty
acids (MUFAs), such as oleic acid, a major constituent
of the myelin membrane, D5D and D6D are required
SREBP-2
Schwann cell
Myelin membrane
Conduction velocity
Axon
SREBP-1c
Fatty acids Cholesterol
Insulin
EFA
Fig. 1. Schematic diagram of the role of Schwann cell SREBPs in
myelination. SREBP-2 predominantly regulates the expression of
enzymes involved in cholesterol synthesis, and to a lesser extent
fatty acid and phospholipid metabolism, necessary for the myelin
membrane. SREBP-1c is under the control of insulin in adults, and
is predominantly involved in myelin fatty acid and phospholipid
metabolism and possibly in direct effects of fatty acids on function-
ing of the axon. EFA, essential fatty acid.
SREBP function in glia–neuron interactions N. Camargo et al.

630 FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS
for the metabolic conversion of c-linolenic acid into
PUFAs and are implicated in reduced nerve conduc-
tion velocity of diabetic patients. In line with this, we
recently reported that expression of SREBP-1c and its
target genes encoding fatty acid synthase and SCD1
are downregulated in Schwann cells in rodent models
of type 1 diabetes. Also, we showed that fasting and
refeeding of rodents strongly affected expression of the
SREBP-1c pathway [3]. In line with this, insulin
affected SREBP-1c expression in Schwann cells by
activation of the SREBP-1c promoter (Fig. 1). Clearly,
the expression of Schwann cell SREBP-1c is affected
by diabetes and nutritional status, indicating that
disturbed SREBP-1c-regulated lipid metabolism may
contribute to the pathophysiology of DPN.
Taken together, the published studies indicate that
fatty acid and phospholipid synthesis necessary for the
formation of the myelin membrane may be regulated
by both Schwann cell SREBP-1c and SREBP-2. Inter-
estingly, SREBP-1c may also be important for func-
tioning of the adult peripheral nerve.
Schwann cell SREBPs – conclusion and
perspective
The temporal expression profile of the SREBPs during
myelination follows the expression of lipogenic
enzymes, and is thereby in keeping with a role for
SREBPs in the synthesis and metabolism of cholesterol
and fatty acids for the myelin membrane. By analogy
with the demonstrated role of the different SREBP iso-

forms in liver [1,8], the action of SREBP-2 in Schwann
cells may predominantly be the transcriptional regula-
tion of cholesterol synthesis, whereas Schwann cell
SREBP-1c may function, possibly in concert with
SREBP-2, in the synthesis and metabolism of fatty
acids and phospholipids (Fig. 1). Whether myelination
is indeed dependent on the action of SREBPs in Schw-
ann cells remains to be determined. Preliminary obser-
vations from our laboratory on mice carrying a
Schwann cell-specific deletion of the SCAP gene (a
gene specifically required for activation of all three
SREBP isoforms [28]) are in line with this hypothe-
sized role (N. Camargo, A. B. Smit & M. H. G. Ver-
heijen, unpublished results). In addition, the elevation
of SREBP-1c expression in the adult peripheral nerve
suggests an active role for Schwann cell SREBP-1c in
functioning of the nerve, a role that may be compro-
mised in the pathophysiology of DPN. The factors reg-
ulating SREBP activity in Schwann cells are so far
unclear. Post-translational activation of SREBPs in
liver is induced by cholesterol depletion. Whether the
activation of SREBPs is also regulated by sterols in
Schwann cells is so far unclear, but would be in line
with the suggestion that synthesis of cholesterol-rich
myelin membrane may lead to transient cytosolic cho-
lesterol depletion [15].
Studies on the transcriptional control of myelin lipid
metabolism have all focused so far on Schwann cells,
and the expression of SREBPs in oligodendrocytes has
not yet been reported. Oligodendrocytes are highly

active in lipid metabolism, and have been demon-
strated to synthesize the cholesterol for the myelin
membrane themselves [29]. This suggests that the
observed roles of SREBPs in Schwann cells may also
have their counterparts in CNS myelination by oligo-
dendrocytes, although this remains to be proven.
Brain lipid metabolism – involvement of
astrocyte SREBPs in neuronal function
The brain is remarkably different in its lipid composi-
tion from other organs. It is highly enriched in PUFAs
and cholesterol. Accordingly, the brain contains about
one-quarter of the total amount of cholesterol in the
body, although it comprises only 2% of total body
weight [30]. This raises the questions of whether there
are specific functions for lipids in the brain and which
cell type(s) are involved in their synthesis.
A wide spectrum of relevant physiological functions
has been attributed to brain lipids. For instance, lipids
may function as building blocks for membranes, and
are therefore important in myelination [10], neurite
outgrowth [31], and synaptogenesis [32]. In addition,
lipids may act as signaling molecules in brain commu-
nication [33]. As such, lipid homeostasis in the nervous
system is an important process that requires a high
level of regulation. Importantly, many studies have
demonstrated that the cells playing a central role in
the synthesis and metabolism of lipids in the brain are
not neurons but glial cells. Whereas the oligodendro-
cytes synthesize lipids as constituents of myelin, as has
been discussed above, astrocytes have been proposed

to supply lipids to neurons and thereby regulate neu-
rite outgrowth and synaptogenesis [32]. Astrocytes are
the most abundant cells in the brain, and are thought
to have multiple functions. They participate in uptake
of nutrients from the blood–brain barrier by surround-
ing the capillary with their end feet [34]. At their other
end, astrocytes are closely associated with the presyn-
aptic and postsynaptic terminals, and as such are part
of the so-called tripartite synapse [7,34]. It has been
estimated that one astrocyte can contact 300–600 neu-
ronal synapses, which led to the proposal that astro-
cytes are able to synchronize a group of synapses [35].
By being in contact with capillaries as well as with
N. Camargo et al. SREBP function in glia–neuron interactions
FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS 631
multiple synapses, astrocytes may supply neurons with
nutrients in accordance with the intensity of their
synaptic activity. In addition, they may act to affect
synaptic function over a long distance by astrocyte–
astrocyte coupling. In the mammalian brain, astrocyte
differentiation takes place in the early postnatal per-
iod, when massive synaptogenesis in the CNS occurs.
In line with this, many studies propose that the glia
supports neuronal survival, enhances neurite out-
growth and increases synaptogenesis. Intriguingly,
recent insights indicate that astrocytes may do this not
only via direct contact [36], but also via secreted
factors, which include fatty acids and cholesterol.
Involvement of astrocyte SREBPs in fatty acid
synthesis – regulation of neurite outgrowth and

synaptic transmission
In a series of studies, Tabernero and Medina have
demonstrated that astrocytes synthesize and release oleic
acid, which in turn induces differentiation of cocultured
neurons. Oleic acid was shown to be enriched in
membrane phospholipids in neuronal growth cones, but
was also shown to stimulate neuronal differentiation
[37]. The synthesis of oleic acid by astrocytes was
demonstrated to be triggered by the transit of albumin,
a fatty acid-binding protein present in the developing
brain, into the astrocytic endoplasmic reticulum
compartment. This transit of albumin correlated with
induction of SREBP-1 activation and subsequent upreg-
ulation of SCD1, an enzyme involved in oleic acid
synthesis, in astrocytes but not neurons [38]. In line with
this, SREBP-1 has been detected in several regions of
the rodent brain at different ages [39]. Together, these
findings indicate a role for astrocyte SREBP-1 in the
synthesis of MUFAs and the subsequent differentiation
of neighboring neurons (Fig. 2).
Importantly, besides MUFAs, PUFAs have also
been demonstrated to strongly stimulate neurite out-
growth [40]. In addition, PUFAs have been demon-
strated to function in synaptic transmission. For
instance, docosahexaenoic acid was demonstrated to
modulate ion currents in isolated hippocampal neu-
rons [26]. Also, arachidonic acid was reported to stim-
ulate neurotransmitter release via direct binding to
syntaxin, a component of the synaptic vesicle release
machinery [41]. Interestingly, Caenorhabditis elegans

lacking D6D, a desaturase essential for long-chain
PUFA synthesis, was found to be defective in neuro-
transmission, probably because of a lack of synaptic
vesicle formation [42]. Whereas large amounts of
PUFAs, predominantly docosahexaenoic acid and ara-
chidonic acid, are found in the brain, the origin of
these is unclear. Multiple sources for PUFAs in the
brain have been described, among which are uptake of
PUFAs from the circulation, either directly through
the diet or via transformation by the liver, and via
local synthesis of PUFAs in glia cells [43]. The devel-
oping brain was found to make its own PUFAs from
essential fatty acids (EFAs) and to incorporate these
PUFAs into phospholipids [43]. Interestingly, Moore
et al. demonstrated that astrocytes, unlike neurons, are
active in desaturation and elongation of EFAs into
PUFAs [44]. In fact, neurons of different brain regions
were found to take up astrocyte-derived PUFAs and
to subsequently incorporate them into phospholipids.
In line with this, the desaturases D5D and D6D were
found to be expressed in astrocytes [45]. By analogy
with the role of SREBP-1 in the regulation of D5D
and D6D expression in liver [46], astrocyte SREBP-1
might be involved in the synthesis of PUFAs, and as
such might play an active role in synaptic communica-
tion. Whether neuronal activity in its turn is able to
regulate SREBP activity in astrocytes is an intriguing
possibility that remains to be determined. In this
respect, it should be noted that the regulation of
SREBP-1 expression and activity in the brain differs

from that in the periphery. Nutritional status and
insulin levels are known to regulate SREBP-1 expres-
sion in Schwann cells in the PNS, as discussed above
[3], but not in the brain [39]. Interestingly, the expres-
Astrocyte
Presynaptic
neuron
Neurite outgrowth
Synaptic plasticity
Postsynaptic
neuron
Synaptogenesis
Fatty acids Cholesterol
SREBPs
Fig. 2. Schematic diagram of the proposed roles of astrocyte
SREBPs in the tripartite synapse. Astrocyte SREBPs regulate the
synthesis of MUFAs, PUFAs and cholesterol, which, after secre-
tion, are bound by neuronal structures and affect neurite
outgrowth, synaptogenesis and synaptic plasticity.
SREBP function in glia–neuron interactions N. Camargo et al.
632 FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS
sion of SREBP-1 in the brain does increase in mice
during aging [39], a phenomenon also observed in the
peripheral nerve [3]. The meaning of this aging-related
increase in SREBP-1 in both the PNS and CNS is at
this moment unclear, but may indicate an elevated
need for local fatty acid metabolism.
In summary, SREBP-1 plays an important role in
the synthesis of MUFAs and PUFAs in astrocytes,
and as such in glia–neuron interactions that involve

fatty acids, such as neurite outgrowth and synaptic
transmission (Fig. 2).
Involvement of astrocyte SREBPs in cholesterol
synthesis – regulation of synaptogenesis and
synaptic function
With the CNS being highly enriched in cholesterol, it
is remarkable that there is almost no transfer of cho-
lesterol-containing lipoproteins from the plasma to the
CNS either in adults or during postnatal development
[30]. Analysis of cholesterol synthesis using radioactive
labeling techniques has shown that almost all of the
cholesterol in the CNS is synthesized in situ [47].
Accordingly, brain expression of SREBP-2 and several
target genes involved in cholesterol synthesis has been
reported [48]. Astrocytes have been demonstrated to
express SREBP-2, which is activated during lipoprotein
assembly [49]. In line with this, astrocytes are the main
apolipoprotein E (ApoE)-producing cells in the CNS
[50], whereas neurons abundantly express ApoE recep-
tors [51]. In addition, transgenic mice lacking neuronal
synthesis of cholesterol, through conditional inactiva-
tion of the squalene synthase in cerebellar neurons, did
not show differences in brain morphology or in behav-
ior [52]. Clearly, transfer of lipids from glia to neurons
plays an important role in neuronal lipid homeostasis.
Most synapses in the developing brain are formed
after the differentiation of astrocytes [53,54], and it
was demonstrated that astrocytes are required for the
formation, maturation and maintenance of synapses in
neuronal cultures [32,53]. The synapse-promoting

signal released by astrocytes in these cultures was,
surprisingly, demonstrated to be cholesterol complexed
to ApoE-containing lipoproteins [55]. Cholesterol is a
major component of neuronal membranes, and is a
component of specialized microdomains, called lipid
rafts, which are required presynaptically for the forma-
tion of synaptic vesicles [56] and postsynaptically for
the clustering and stability of receptors [57]. These
findings argue for a prominent role of SREBP-2 and
astrocyte-derived cholesterol in synaptic development
and function. In addition, it may be speculated that,
via similar mechanisms, astrocytes potentially regulate
synaptic plasticity in the adult brain. In line with this,
the ApoE receptor LDL-receptor related protein has
been shown to play an active role in synaptic plasticity
in the mouse hippocampus [51], whereas pharmacolog-
ical inhibition of cholesterol synthesis inhibits synaptic
plasticity in rat hippocampal slices [58]. Finally, treat-
ment of human astrocytoma cells lines with antipsy-
chotic and antidepressant drugs induced activation of
SREBPs and subsequent cholesterol synthesis, whereas
these drugs had little effect on the SREBP pathway in
human neuronal cell lines, suggesting that the action
of such drugs on synaptic transmission may be primar-
ily on astrocytes [59]. Taken together, these findings
imply that SREBPs in astrocytes may function in the
controlled supply of cholesterol to synaptic structures,
and thereby contribute to the formation and behavior
of lipid rafts and therefore to synaptic function
(Fig. 2).

A proposed role for astrocyte SREBPs in neuronal
function
The relative autonomy of the CNS in metabolism of
cholesterol and fatty acids, together with the impor-
tance of these lipids for neuronal development and
synaptic functioning, requires a high activity of lipid
synthesis in the brain. By analogy to the liver, where
SREBP activity is involved in lipid synthesis for supply
to the periphery, we propose that SREBPs in astro-
cytes are involved in lipid synthesis for supply to neu-
rons (Fig. 2). Whether neurons are indeed dependent
on astrocyte-derived lipids, and as such rely on the
action of SREBPs in astrocytes, or whether other lipid
sources are involved remains to be determined. This
will probably require experimental interference with
astrocyte lipid synthesis.
Notably, many brain diseases are associated with
lipid metabolism dysfunction. For instance, Niemann–
Pick disease type C, which causes cognitive deficits and
motor impairment in young children, has been linked
to defective cholesterol transport in astrocytes [60]. In
addition, recent studies have shown a strong connec-
tion between lipid metabolism, ApoE and the neurode-
generative loss of synaptic plasticity in Alzheimer’s
disease [61]. The lipids shown to be involved include
cholesterol [61] and PUFAs [62]. Intriguingly, it was
found that the risk of Alzheimer’s disease is lower in
humans carrying a specific polymorphism in SREBP-
1a [63]. Finally, for Huntington’s disease, it was dem-
onstrated that expression of the mutant Huntington

protein in astrocytes contributes to neuronal damage
[64], whereas others have demonstrated that this
Huntington protein leads to reduced SREBP matura-
N. Camargo et al. SREBP function in glia–neuron interactions
FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS 633
tion and consequent reduced cholesterol synthesis [65].
Taken together, these findings are in line with a
potential role of astrocyte-derived lipids in the forma-
tion, maturation and functioning of synapses, in both
health and disease.
In summary, SREBPs seem to play an important
role in the lipid metabolism of glia of both the PNS
and the CNS, and act in diverse processes involving
glia–neuron interaction such as myelination, neuronal
development, neurite outgrowth, synaptogenesis and
synaptic transmission. Accordingly, glia SREBPs may
function as a control point of neural function. Identifi-
cation of the (neuronal) pathways regulating glia
SREBP activity will enhance our understanding of the
functioning of the nervous system, and possibly
provide therapeutic targets for neurological disorders
associated with lipids.
Acknowledgements
The authors apologize to colleagues whose relevant
work could not be cited because of space restrictions.
We thank R. Chrast for critical reading of the manu-
script. N. Camargo is supported by a Marie Curie
Host Fellowship (grant EST-2005-020919).
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