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: 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. 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). References 1 Horton JD, Goldstein JL & Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109, 1125– 1131. 2 Shimano H (2002) Sterol regulatory element-binding protein family as global regulators of lipid synthetic genes in energy metabolism. Vitam Horm 65, 167–194. 3 de Preux AS, Goosen K, Zhang W, Sima AA, Shimano H, Ouwens DM, Diamant M, Hillebrands JL, Rozing J, Lemke G et al. (2007) SREBP-1c expression in Schw- ann cells is affected by diabetes and nutritional status. Mol Cell Neurosci 35, 525–534. 4 Jurevics HA & Morell P (1994) Sources of cholesterol for kidney and nerve during development. J Lipid Res 35, 112–120. 5 Morell P & Jurevics H (1996) Origin of cholesterol in myelin. Neurochem Res 21, 463–470. 6 Rechthand E & Rapoport SI (1987) Regulation of the microenvironment of peripheral nerve: role of the blood–nerve barrier. Prog Neurobiol 28, 303–343. 7 Halassa MM, Fellin T & Haydon PG (2007) The tripar- tite synapse: roles for gliotransmission in health and dis- ease. Trends Mol Med 13, 54–63. 8 Shimano H, Amemiya-Kudo M, Takahashi A, Kato T, Ishikawa M & Yamada N (2007) Sterol regulatory ele- ment-binding protein-1c and pancreatic beta-cell dys- function. Diabetes Obes Metab 9 (Suppl. 2), 133–139. 9 Verheijen MH, Chrast R, Burrola P & Lemke G (2003) Local regulation of fat metabolism in peripheral nerves. Genes Dev 17, 2450–2464. 10 Garbay B, Heape AM, Sargueil F & Cassagne C (2000) Myelin synthesis in the peripheral nervous system. Prog Neurobiol 61, 267–304. 11 Webster HD (1971) The geometry of peripheral myelin sheaths during their formation and growth in rat sciatic nerves. J Cell Biol 48, 348–367. 12 Goodrum JF, Fowler KA, Hostettler JD & Toews AD (2000) Peripheral nerve regeneration and choles- terol reutilization are normal in the low-density lipo- protein receptor knockout mouse. J Neurosci Res 59, 581–586. 13 Harry GJ, Goodrum JF, Bouldin TW, Wagner-Recio M, Toews AD & Morell P (1989) Tellurium-induced neuropathy: metabolic alterations associated with demy- elination and remyelination in rat sciatic nerve. J Neu- rochem 52, 938–945. 14 Wiley-Livingston CA & Ellisman MH (1982) Return of axonal and glial membrane specializations during remyelination after tellurium-induced demyelination. J Neurocytol 11, 65–80. 15 Fu Q, Goodrum JF, Hayes C, Hostettler JD, Toews AD & Morell P (1998) Control of cholesterol biosynthe- sis in Schwann cells. J Neurochem 71, 549–555. 16 Nagarajan R, Le N, Mahoney H, Araki T & Milbrandt J (2002) Deciphering peripheral nerve myelination by using Schwann cell expression profiling. Proc Natl Acad Sci USA 99, 8998–9003. 17 Salles J, Sargueil F, Knoll-Gellida A, Witters LA, Cas- sagne C & Garbay B (2003) Acetyl-CoA carboxylase and SREBP expression during peripheral nervous sys- tem myelination. Biochim Biophys Acta 1631, 229–238. 18 Leblanc SE, Srinivasan R, Ferri C, Mager GM, Gillian- Daniel AL, Wrabetz L & Svaren J (2005) Regulation of cholesterol ⁄ lipid biosynthetic genes by Egr2 ⁄ Krox20 during peripheral nerve myelination. J Neurochem 93, 737–748. 19 Nagarajan R, Svaren J, Le N, Araki T, Watson M & Milbrandt J (2001) EGR2 mutations in inherited neur- opathies dominant-negatively inhibit myelin gene expression. Neuron 30, 355–368. 20 Garbay B, Boiron-Sargueil F, Shy M, Chbihi T, Jiang H, Kamholz J & Cassagne C (1998) Regulation of oleoyl-CoA synthesis in the peripheral nervous system: demonstration of a link with myelin synthesis. J Neuro- chem 71, 1719–1726. 21 Salles J, Sargueil F, Knoll-Gellida A, Witters LA, Shy M, Jiang H, Cassagne C & Garbay B (2002) Fatty acid synthase expression during peripheral nervous system myelination. Brain Res Mol Brain Res 101, 52–58. SREBP function in glia–neuron interactions N. Camargo et al. 634 FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS 22 Jansen GA, Ofman R, Ferdinandusse S, Ijlst L, Muij- sers AO, Skjeldal OH, Stokke O, Jakobs C, Besley GT, Wraith JE et al. (1997) Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet 17, 190–193. 23 Nadra K, de Preux Charles AS, Medard JJ, Hendriks WT, Han GS, Gres S, Carman GM, Saulnier-Blache JS, Verheijen MH & Chrast R (2008) Phosphatidic acid mediates demyelination in Lpin1 mutant mice. Genes Dev 22, 1647–1661. 24 Sima AA (2003) New insights into the metabolic and molecular basis for diabetic neuropathy. Cell Mol Life Sci 60, 2445–2464. 25 Horrobin DF (1997) Essential fatty acids in the man- agement of impaired nerve function in diabetes. Diabe- tes 46 (Suppl. 2), S90–S93. 26 Vreugdenhil M, Bruehl C, Voskuyl RA, Kang JX, Leaf A & Wadman WJ (1996) Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons. Proc Natl Acad Sci USA 93, 12559–12563. 27 Nakamura MT & Nara TY (2002) Gene regulation of mammalian desaturases. Biochem Soc Trans 30, 1076– 1079. 28 Matsuda M, Korn BS, Hammer RE, Moon YA, Kom- uro R, Horton JD, Goldstein JL, Brown MS & Shi- momura I (2001) SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev 15, 1206–1216. 29 Saher G, Brugger B, Lappe-Siefke C, Mobius W, Tozawa R, Wehr MC, Wieland F, Ishibashi S & Nave KA (2005) High cholesterol level is essential for myelin membrane growth. Nat Neurosci 8, 468– 475. 30 Dietschy JM & Turley SD (2004) Thematic review ser- ies: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 45, 1375–1397. 31 Vance JE, Hayashi H & Karten B (2005) Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol 16, 193–212. 32 Slezak M & Pfrieger FW (2003) New roles for astro- cytes: regulation of CNS synaptogenesis. Trends Neuro- sci 26, 531–535. 33 Bazan NG (2003) Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res 44, 2221–2233. 34 Haydon PG & Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86, 1009–1031. 35 Halassa MM, Fellin T, Takano H, Dong JH & Haydon PG (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27, 6473–6477. 36 Hama H, Hara C, Yamaguchi K & Miyawaki A (2004) PKC signaling mediates global enhancement of excit- atory synaptogenesis in neurons triggered by local contact with astrocytes. Neuron 41, 405–415. 37 Rodriguez-Rodriguez RA, Tabernero A, Velasco A, Lavado EM & Medina JM (2004) The neurotrophic effect of oleic acid includes dendritic differentiation and the expression of the neuronal basic helix–loop– helix transcription factor NeuroD2. J Neurochem 88, 1041–1051. 38 Tabernero A, Granda B, Medina A, Sanchez-Abarca LI, Lavado E & Medina JM (2002) Albumin promotes neuronal survival by increasing the synthesis and release of glutamate. J Neurochem 81, 881–891. 39 Okamoto K, Kakuma T, Fukuchi S, Masaki T, Sakata T & Yoshimatsu H (2006) Sterol regulatory element binding protein (SREBP)-1 expression in brain is affected by age but not by hormones or metabolic changes. Brain Res 1081, 19–27. 40 Darios F & Davletov B (2006) Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3. Nature 440, 813–817. 41 Connell E, Darios F, Broersen K, Gatsby N, Peak- Chew SY, Rickman C & Davletov B (2007) Mechanism of arachidonic acid action on syntaxin-Munc18. EMBO Rep 8, 414–419. 42 Lesa GM, Palfreyman M, Hall DH, Clandinin MT, Rudolph C, Jorgensen EM & Schiavo G (2003) Long chain polyunsaturated fatty acids are required for effi- cient neurotransmission in C. elegans. J Cell Sci 116, 4965–4975. 43 Green P & Yavin E (1993) Elongation, desaturation, and esterification of essential fatty acids by fetal rat brain in vivo. J Lipid Res 34, 2099–2107. 44 Moore SA (2001) Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro. J Mol Neuro- sci 16, 195–200. 45 Innis SM & Dyer RA (2002) Brain astrocyte synthesis of docosahexaenoic acid from n-3 fatty acids is limited at the elongation of docosapentaenoic acid. J Lipid Res 43, 1529–1536. 46 Matsuzaka T, Shimano H, Yahagi N, Amemiya-Kudo M, Yoshikawa T, Hasty AH, Tamura Y, Osuga J, Okazaki H, Iizuka Y et al. (2002) Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expres- sion by SREBP-1 and PPARalpha. J Lipid Res 43, 107–114. 47 Turley SD, Burns DK, Rosenfeld CR & Dietschy JM (1996) Brain does not utilize low density lipoprotein- cholesterol during fetal and neonatal development in the sheep. J Lipid Res 37, 1953–1961. 48 Tarr PT & Edwards PA (2008) ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2. J Lipid Res 49, 169–182. 49 Ito J, Nagayasu Y, Kato K, Sato R & Yokoyama S (2002) Apolipoprotein A-I induces translocation of 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 635 cholesterol, phospholipid, and caveolin-1 to cytosol in rat astrocytes. J Biol Chem 277, 7929–7935. 50 Boyles JK, Pitas RE, Wilson E, Mahley RW & Taylor JM (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyeli- nating glia of the peripheral nervous system. J Clin Invest 76, 1501–1513. 51 Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M & Bu G (2000) Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. J Neurosci 20, 542–549. 52 Funfschilling U, Saher G, Xiao L, Mobius W & Nave KA (2007) Survival of adult neurons lacking cholesterol synthesis in vivo. BMC Neurosci 8 , 1–9. 53 Ullian EM, Sapperstein SK, Christopherson KS & Barres BA (2001) Control of synapse number by glia. Science 291, 657–661. 54 Pfrieger FW & Barres BA (1996) New views on syn- apse–glia interactions. Curr Opin Neurobiol 6, 615–621. 55 Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A & Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357. 56 Thiele C, Hannah MJ, Fahrenholz F & Huttner WB (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2, 42–49. 57 Allen JA, Halverson-Tamboli RA & Rasenick MM (2007) Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 8, 128–140. 58 Matthies H Jr, Schulz S, Hollt V & Krug M (1997) Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Neuroscience 79, 341–346. 59 Ferno J, Skrede S, Vik-Mo AO, Havik B & Steen VM (2006) Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: marked differences between various antipsychotic drugs. BMC Neurosci 7, 69–80. 60 Patel SC, Suresh S, Kumar U, Hu CY, Cooney A, Blanchette-Mackie EJ, Neufeld EB, Patel RC, Brady RO, Patel YC et al. (1999) Localization of Niemann– Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann–Pick type C disease. Proc Natl Acad Sci USA 96, 1657–1662. 61 Poirier J (2003) Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol Med 9, 94–101. 62 Calon F, Lim GP, Yang F, Morihara T, Teter B, Ube- da O, Rostaing P, Triller A, Salem N Jr, Ashe KH et al. (2004) Docosahexaenoic acid protects from den- dritic pathology in an Alzheimer’s disease mouse model. Neuron 43, 633–645. 63 Spell C, Kolsch H, Lutjohann D, Kerksiek A, Hent- schel F, Damian M, von Bergmann K, Rao ML, Maier W & Heun R (2004) SREBP-1a polymorphism influences the risk of Alzheimer’s disease in carriers of the ApoE4 allele. Dement Geriatr Cogn Disord 18, 245–249. 64 Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH & Li XJ (2005) Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J Cell Biol 171, 1001–1012. 65 Valenza M, Rigamonti D, Goffredo D, Zuccato C, Fenu S, Jamot L, Strand A, Tarditi A, Woodman B, Racchi M et al. (2005) Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neuro- sci 25, 9932–9939. SREBP function in glia–neuron interactions N. Camargo et al. 636 FEBS Journal 276 (2009) 628–636 ª 2008 The Authors Journal compilation ª 2008 FEBS . 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. acid synthase expression during peripheral nervous system myelination. Brain Res Mol Brain Res 101, 52–58. SREBP function in glia–neuron interactions N. Camargo