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
Trang 1SREBPs: 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: mark.verheijen@cncr.vu.nl
(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.
Trang 2gene 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 propro-tein-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 cholinter-esterol 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
Trang 3that, 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
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.
Trang 4for 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 postsynpresyn-aptic 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
Trang 5multiple 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 Postsynapticneuron
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.
Trang 6sion 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 neuneu-rons 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
Trang 7matura-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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