JOURNAL OF NEUROCHEMISTRY
| 2014 | 129 | 363–365
doi: 10.1111/jnc.12692
Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA Read the full article ‘Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia’ on page 400.
In most organisms, carbon is a very abundant element, yet in mammalian species this very abundant element is preciously conserved and recycled. I first encountered carbon recycling in experiments in which I was incubating L-cell fibroblasts with [1-14C]oleic acid (18 : 1n-9) and found trace amounts of this fatty acid associated with cholesterol and cholesteryl esters. Finding radioactivity in cholesteryl esters is rather easy to explain as the fatty acid tracer could be esterified onto the hydroxyl group on the third carbon of cholesterol. The explanation for finding radioactivity in cholesterol was not readily apparent at that time and it remained a mystery as I underappreciated the capability of cells to change the biochemical nature of carbon containing molecules such as fatty acids. However, with experience comes wisdom and soon I began to understand that carbon recycling occurs as fatty acids are subjected to b-oxidation and the carbons recycled and used in other biosynthetic reactions (Fig. 1). What some know, but many do not is that carbon recycling is very efficient, rapid, and occurs in different tissues (Cunnane et al. 2000; DeMar et al. 2005; Golovko and Murphy 2006; Golovko et al. 2006; Murphy et al. 2008). An example of the rapidity is in livers from rats infused with [14-14C]22 : 1n-9 where this tracer is rapidly used over 5–10 min to make saturated fatty acids that are found in triacylglycerols that are more than likely exported in very low-density lipoproteins into the plasma (Murphy et al. 2008). This process occurs in liver to a greater extent than heart, but in brain this process also occurs. In fact in the [14-14C]22:1n-9 infused rats, the brain takes the tracer and chain shortens it as well as using it for the apparent synthesis de novo of saturated fatty acids (Golovko and Murphy 2006). This is indicative that the brain of the adult animal retains the capacity to recycle carbon into saturated fatty acids, something that is well established in developing rats that convert dietary polyunsaturated fatty acids to form saturated fatty
acids and cholesterol in the brain (Menard et al. 1998; Cunnane et al. 1999, 2000). This process can only occur via b-oxidation and recycling the carbon units. However, the rapidity of carbon recycling is often underappreciated not only by lipid biochemists, but for all of those who think lipid metabolism occurs only on a biochemical glacial time scale of weeks and months rather than minutes that is required for lipid-mediated signal transduction and metabolism. However, does this process occur in higher order species such as non-human primates? Yes. Fatty acid carbon recycling of dietary polyunsaturated fatty acids occurs in non-human primates (Sheaff Greiner et al. 1996), where these fatty acids are converted to cholesterol and saturated fatty acids. This occurs in the developing and in the adult brain, demonstrating the importance of b-oxidation in the brain to provide carbons for use by other synthetic processes. The Rapoport group some years ago demonstrated the importance of b-oxidation in providing carbon units for the synthesis of neurotransmitters such as glutamate (Miller et al. 1987). This linked brain fatty acid metabolism to the production of key neurotransmitters that are produced from Krebs cycle intermediates and absolutely critical in brain function. Some years ago, the excitotoxicity hypothesis became the foundation as the unifying mechanism for the pathophysiology resulting from ischemia and neurotrauma (Rothman 1984; Rothman and Olney 1986; Choi et al. 1987). Whether the nature of the insult was hypoxic, ischemic, or physical brain injury, the premise is that excitatory amino acids are
Received February 13, 2014; accepted February 17, 2014. Address correspondence and reprint requests to Eric J. Murphy, Department of Basic Sciences, School of Medicine and Health Science, University of North Dakota, 501 N. Columbia Rd., Room 3700, Grand Forks, ND 58202-9037, USA. E-mail: [email protected]
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
363
364
Review
Krebs cycle + FAS
HYPOXIA
Glutamate
Fatty acids
β-oxidation + Krebs cycle Fig. 1 Fatty acids are converted through a combination of b-oxidation and carbons entering the Krebs cycle to glutamate (Miller et al. 1987). This links fatty acids that rapidly undergo b-oxidation to the formation of amino acid neurotransmitters such as glutamate. Golovko and colleagues demonstrate that a combined reaction of Krebs cycle and fatty acid synthase converts glutamate to fatty acids and that this process is up-regulated in neurons under hypoxic conditions.
released into the synapses combined with a concomitant reduced uptake of these transmitters, which results in the exacerbation of calcium influx into cells, a collapse in ATP levels, and ultimately in a profound amount of neuronal death. In a nutshell, releasing a whole lot of glutamate has a really bad outcome for the brain. We also know from classic work that fatty acids are released during these traumatic events (Bazan 1970, 1971; Ikeda et al. 1986; Yoshida et al. 1986; Lin et al. 1991) and that this increase in fatty acids reduces the ability of astrocytes to take up and sequester the excitatory amino acids from the extracellular environment (Rhoads et al. 1982; Chan et al. 1983; Volterra et al. 1992). This creates a vicious cycle and may ultimately be the reason why the brain is so susceptible to injury, but also provides an inseparable link between fatty acids and amino acid neurotransmitters. So, what does any of this have to do with the idea that carbon cycling is perhaps a bit more circular than we first thought? Well in some very exciting work from the Golovko group (Brose et al. 2013), they demonstrate for the first time that neurons, but only neurons, have a large increase in the capacity to convert glutamate under hypoxic conditions to saturated and monounsaturated fatty acids (Fig. 1). This process has two potentially beneficial outcomes for the cell. First, the formation of fatty acids will use reducing power that is built up under these conditions as NADH and NADPH that are formed via the shift of glucose flux from acetyl-CoA formation to lactate formation. This limits the ability of the neuron to continue to use glycolysis efficiently as NAD+ becomes limiting, hence by using NADH in fatty acid biosynthesis de novo, NAD+ as well as NADP+ are produced. Second, I have already highlighted the excitatory amino acid hypothesis as a unifying mechanism for neuronal injury. This
newly elucidated mechanism offers an alternative metabolic pathway for glutamate, thereby reducing its potential toxicity as it is converted to fatty acids under hypoxic conditions. In essence, this newly discovered process really demonstrates a novel mechanism by which neurons can protect themselves under hypoxic conditions from glutamate toxicity. This is truly ground breaking and offers a new lens through which to view the concept of how the brain, particularly neurons, deal with injury. Hypoxia is often associated with brain injury because of the vasospasm and spreading depression ultimately reducing blood flow in the brain. Whether the insult is ischemic in nature or associated with traumatic brain injury, hypoxia often is a resulting event. What makes this work truly exciting is that neurons, but not astrocytes, have the ability to take glutamate and make saturated and monounsaturated fatty acids. Hence, neurons, the most susceptible cells to hypoxia (Goldberg et al. 1986), are capable of using this pathway to remove glutamate from the extracellular environment, whereas much less susceptible cells, astrocytes (Haun et al. 1992), do not have this capacity. The elegance of these studies is that the Golovko group examined if this unique form of carbon recycling occurs across different cell types, including Hep2G and PC-12 cells. In many cells types, both primary and models for primary cells, hypoxia results in a profound reduction in the use of glutamate for fatty acid biosynthesis. This includes rat primary cortical astrocytes and BV-2 cells, a murine cell line used as a model for microglia. However, in differentiated SH-SY5Y cells, a common human neuronal cell model, there is a marked increase in the use of glutamate to form fatty acids under hypoxic conditions. Primary rat cortical neurons also increase the conversion of glutamate to fatty acids under hypoxic conditions, suggesting that this process is perhaps universal to neurons, but not to all neural cells. I find this latter observation to be of interest as astrocytes are linked to both glutamate uptake and are key cells involved in brain lipid biosynthesis (Moore et al. 1991; Hirsch-Reinshagen et al. 2004; Nieweg et al. 2009; Pfrieger and Ungerer 2011). Hence, the lack of seeing an upregulation of this conversion in astrocytes during hypoxia is intriguing. Nonetheless, the most exciting part of this finding is that there is substantial evidence presented that only neurons increase this conversion in the brain under hypoxia conditions. So, now we know that the cycling of carbon from fatty acids to glutamate occurs and under hypoxic conditions broadly associated with neurotrauma, that carbons from glutamate are recycled to fatty acids. This observation creates new excitement for understanding how carbons flow under various conditions from glucose to fatty acid to amino acids and back. While certainly questions remain as to the underlying benefits to the neurons with regard to various potential protective mechanisms, e.g., a shift in NADH to NAD+ or reduced glutamate toxicity, this discovery opens
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
Review
our eyes to a new potential mechanism that is critical in protecting neurons during traumatic events.
Acknowledgments The author is an editor of the Journal of Neurochemistry.
References Bazan N. G. (1970) Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim. Biophys. Acta 218, 1–10. Bazan N. G. (1971) Changes in free fatty acids of brain by drug-induced convulsions, electroshock and anesthesia. J. Neurochem. 18, 1379–1385. Brose S., Marquardt A. L. and Golovko M. Y. (2013) Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia. J. Neurochem. 129, 400–412. Chan P. H., Kerlan R. and Fishman R. A. (1983) Reductions of Γ-aminobutyric acid and glutamate uptake and (Na+, K+)-ATPase activity in brain slices and synaptosomes by arachidonic acid. J. Neurochem. 40, 309–316. Choi D. W., Maulucci-Gedde M. and Kriegstein A. R. (1987) Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368. Cunnane S. C., Menard C. R., Likhodii S. S., Brenna J. T. and Crawford M. A. (1999) Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and a-linolenate. Prostaglandins Leukot. Essent. Fatty Acids 60, 387–392. Cunnane S. C., Trotti D. and Ryan M. A. (2000) Specific linoleate deficiency in the rat does not prevent substantial carbon recycling from [14C]linoleate into sterols. J. Lipid Res. 41, 1808–1811. DeMar J. C., Jr, Ma K., Chang L., Bell J. M. and Rapoport S. I. (2005) a-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid. J. Neurochem. 94, 1063–1076. Goldberg W. J., Kadingo R. M. and Barrett J. N. (1986) Effects of ischemia-like conditions on cultured neurons: protection by low Na+, Low Ca2+ solutions. J. Neurosci. 6, 3144–3151. Golovko M. Y. and Murphy E. J. (2006) Uptake and metabolism of plasma derived euricic acid by rat brain. J. Lipid Res. 47, 1289–1297. Golovko M. Y., Rosenberger T. A., Færgeman N. J., Feddersen S., Cole N. B., Pribill I., Berger J., Nussbaum R. L. and Murphy E. J. (2006) Acyl-CoA synthetase activity links wild-type but not mutant a-synuclein to brain arachidonate metabolism. Biochemistry 45, 6956–6966. Haun S. E., Murphy E. J., Bates C. M. and Horrocks L. A. (1992) Extracellular calcium is a mediator of astroglial injury during combined glucose-oxygen deprivation. Brain Res. 593, 45–50. Hirsch-Reinshagen V., Zhou S., Burgess B. L., Bernier L., McIsaac S. A., Chan J. Y., Tansley G. H., Cohn J. S., Hayden M. R. and
365
Wellington C. L. (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J. Biol. Chem. 279, 41197–41207. Ikeda M., Yoshida S., Busto R., Santiso M. and Ginsberg M. D. (1986) Polyphosphoinositides as a probable source of brain free fatty acids accumulated at the onset of ischemia. J. Neurochem. 47, 123–132. Lin T. N., Liu T. H., Xu J., Hsu C. Y. and Sun G. Y. (1991) Brain polyphosphoinositide metabolism during focal ischemia in rat cortex. Stroke 22, 495–498. Menard C. R., Goodman K. J., Corso T. N., Brenna J. T. and Cunnane S. C. (1998) Recycling of carbon into lipids synthesized de novo is a quantitatively important pathway of a-[U-13C] linolenate utilization in the developing rat brain. J. Neurochem. 71, 2151–2158. Miller J. C., Gnaedinger J. M. and Rapoport S. I. (1987) Utilization of plasma fatty acid in rat brain: distribution of [14C]palmitate between oxidative and synthetic pathways. J. Neurochem. 49, 1507–1514. Moore S. A., Yoder E., Murphy S., Dutton G. R. and Spector A. A. (1991) Astrocytes, not neurons produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6). J. Neurochem. 56, 518–524. Murphy C. C., Murphy E. J. and Golovko M. Y. (2008) Eurcic acid is differentially taken up and metabolized in rat liver and heart. Lipids 43, 391–400. Nieweg K., Schaller H. and Pfrieger F. W. (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J. Neurochem. 109, 125–134. Pfrieger F. W. and Ungerer N. (2011) Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371. Rhoads D. E., Kaplan M. A., Peterson N. A. and Raghupathy E. (1982) Effects of free fatty acids on synaptosomal amino acid uptake systems. J. Neurochem. 38, 1255–1260. Rothman S. (1984) Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J. Neurosci. 4, 1884–1891. Rothman S. M. and Olney J. W. (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19, 105–111. Sheaff Greiner R. C., Zhang Q., Goodman K. J. and Giussani D. A. (1996) Linoleate, a-linolenate, and docosahexaenoate recycling into saturated and monounsaturated fatty acids is a major pathway in pregnant or lactating adults and fetal or infant rhesus monkeys. J. Lipid Res. 37, 2675–2686. Volterra A., Trotti D., Cassutti P., Tromba C., Salvaggio A., Melcangi R. C. and Racagni G. (1992) High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes. J. Neurochem. 59, 600–606. Yoshida S., Ideda M., Busto R., Santiso M., Martinez E. and Ginsberg M. D. (1986) Cerebral phosphoinositide, triacylglycerol, and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J. Neurochem. 47, 744–757.
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
| 2014 | 129 | 363–365
doi: 10.1111/jnc.12692
Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA Read the full article ‘Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia’ on page 400.
In most organisms, carbon is a very abundant element, yet in mammalian species this very abundant element is preciously conserved and recycled. I first encountered carbon recycling in experiments in which I was incubating L-cell fibroblasts with [1-14C]oleic acid (18 : 1n-9) and found trace amounts of this fatty acid associated with cholesterol and cholesteryl esters. Finding radioactivity in cholesteryl esters is rather easy to explain as the fatty acid tracer could be esterified onto the hydroxyl group on the third carbon of cholesterol. The explanation for finding radioactivity in cholesterol was not readily apparent at that time and it remained a mystery as I underappreciated the capability of cells to change the biochemical nature of carbon containing molecules such as fatty acids. However, with experience comes wisdom and soon I began to understand that carbon recycling occurs as fatty acids are subjected to b-oxidation and the carbons recycled and used in other biosynthetic reactions (Fig. 1). What some know, but many do not is that carbon recycling is very efficient, rapid, and occurs in different tissues (Cunnane et al. 2000; DeMar et al. 2005; Golovko and Murphy 2006; Golovko et al. 2006; Murphy et al. 2008). An example of the rapidity is in livers from rats infused with [14-14C]22 : 1n-9 where this tracer is rapidly used over 5–10 min to make saturated fatty acids that are found in triacylglycerols that are more than likely exported in very low-density lipoproteins into the plasma (Murphy et al. 2008). This process occurs in liver to a greater extent than heart, but in brain this process also occurs. In fact in the [14-14C]22:1n-9 infused rats, the brain takes the tracer and chain shortens it as well as using it for the apparent synthesis de novo of saturated fatty acids (Golovko and Murphy 2006). This is indicative that the brain of the adult animal retains the capacity to recycle carbon into saturated fatty acids, something that is well established in developing rats that convert dietary polyunsaturated fatty acids to form saturated fatty
acids and cholesterol in the brain (Menard et al. 1998; Cunnane et al. 1999, 2000). This process can only occur via b-oxidation and recycling the carbon units. However, the rapidity of carbon recycling is often underappreciated not only by lipid biochemists, but for all of those who think lipid metabolism occurs only on a biochemical glacial time scale of weeks and months rather than minutes that is required for lipid-mediated signal transduction and metabolism. However, does this process occur in higher order species such as non-human primates? Yes. Fatty acid carbon recycling of dietary polyunsaturated fatty acids occurs in non-human primates (Sheaff Greiner et al. 1996), where these fatty acids are converted to cholesterol and saturated fatty acids. This occurs in the developing and in the adult brain, demonstrating the importance of b-oxidation in the brain to provide carbons for use by other synthetic processes. The Rapoport group some years ago demonstrated the importance of b-oxidation in providing carbon units for the synthesis of neurotransmitters such as glutamate (Miller et al. 1987). This linked brain fatty acid metabolism to the production of key neurotransmitters that are produced from Krebs cycle intermediates and absolutely critical in brain function. Some years ago, the excitotoxicity hypothesis became the foundation as the unifying mechanism for the pathophysiology resulting from ischemia and neurotrauma (Rothman 1984; Rothman and Olney 1986; Choi et al. 1987). Whether the nature of the insult was hypoxic, ischemic, or physical brain injury, the premise is that excitatory amino acids are
Received February 13, 2014; accepted February 17, 2014. Address correspondence and reprint requests to Eric J. Murphy, Department of Basic Sciences, School of Medicine and Health Science, University of North Dakota, 501 N. Columbia Rd., Room 3700, Grand Forks, ND 58202-9037, USA. E-mail: [email protected]
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
363
364
Review
Krebs cycle + FAS
HYPOXIA
Glutamate
Fatty acids
β-oxidation + Krebs cycle Fig. 1 Fatty acids are converted through a combination of b-oxidation and carbons entering the Krebs cycle to glutamate (Miller et al. 1987). This links fatty acids that rapidly undergo b-oxidation to the formation of amino acid neurotransmitters such as glutamate. Golovko and colleagues demonstrate that a combined reaction of Krebs cycle and fatty acid synthase converts glutamate to fatty acids and that this process is up-regulated in neurons under hypoxic conditions.
released into the synapses combined with a concomitant reduced uptake of these transmitters, which results in the exacerbation of calcium influx into cells, a collapse in ATP levels, and ultimately in a profound amount of neuronal death. In a nutshell, releasing a whole lot of glutamate has a really bad outcome for the brain. We also know from classic work that fatty acids are released during these traumatic events (Bazan 1970, 1971; Ikeda et al. 1986; Yoshida et al. 1986; Lin et al. 1991) and that this increase in fatty acids reduces the ability of astrocytes to take up and sequester the excitatory amino acids from the extracellular environment (Rhoads et al. 1982; Chan et al. 1983; Volterra et al. 1992). This creates a vicious cycle and may ultimately be the reason why the brain is so susceptible to injury, but also provides an inseparable link between fatty acids and amino acid neurotransmitters. So, what does any of this have to do with the idea that carbon cycling is perhaps a bit more circular than we first thought? Well in some very exciting work from the Golovko group (Brose et al. 2013), they demonstrate for the first time that neurons, but only neurons, have a large increase in the capacity to convert glutamate under hypoxic conditions to saturated and monounsaturated fatty acids (Fig. 1). This process has two potentially beneficial outcomes for the cell. First, the formation of fatty acids will use reducing power that is built up under these conditions as NADH and NADPH that are formed via the shift of glucose flux from acetyl-CoA formation to lactate formation. This limits the ability of the neuron to continue to use glycolysis efficiently as NAD+ becomes limiting, hence by using NADH in fatty acid biosynthesis de novo, NAD+ as well as NADP+ are produced. Second, I have already highlighted the excitatory amino acid hypothesis as a unifying mechanism for neuronal injury. This
newly elucidated mechanism offers an alternative metabolic pathway for glutamate, thereby reducing its potential toxicity as it is converted to fatty acids under hypoxic conditions. In essence, this newly discovered process really demonstrates a novel mechanism by which neurons can protect themselves under hypoxic conditions from glutamate toxicity. This is truly ground breaking and offers a new lens through which to view the concept of how the brain, particularly neurons, deal with injury. Hypoxia is often associated with brain injury because of the vasospasm and spreading depression ultimately reducing blood flow in the brain. Whether the insult is ischemic in nature or associated with traumatic brain injury, hypoxia often is a resulting event. What makes this work truly exciting is that neurons, but not astrocytes, have the ability to take glutamate and make saturated and monounsaturated fatty acids. Hence, neurons, the most susceptible cells to hypoxia (Goldberg et al. 1986), are capable of using this pathway to remove glutamate from the extracellular environment, whereas much less susceptible cells, astrocytes (Haun et al. 1992), do not have this capacity. The elegance of these studies is that the Golovko group examined if this unique form of carbon recycling occurs across different cell types, including Hep2G and PC-12 cells. In many cells types, both primary and models for primary cells, hypoxia results in a profound reduction in the use of glutamate for fatty acid biosynthesis. This includes rat primary cortical astrocytes and BV-2 cells, a murine cell line used as a model for microglia. However, in differentiated SH-SY5Y cells, a common human neuronal cell model, there is a marked increase in the use of glutamate to form fatty acids under hypoxic conditions. Primary rat cortical neurons also increase the conversion of glutamate to fatty acids under hypoxic conditions, suggesting that this process is perhaps universal to neurons, but not to all neural cells. I find this latter observation to be of interest as astrocytes are linked to both glutamate uptake and are key cells involved in brain lipid biosynthesis (Moore et al. 1991; Hirsch-Reinshagen et al. 2004; Nieweg et al. 2009; Pfrieger and Ungerer 2011). Hence, the lack of seeing an upregulation of this conversion in astrocytes during hypoxia is intriguing. Nonetheless, the most exciting part of this finding is that there is substantial evidence presented that only neurons increase this conversion in the brain under hypoxia conditions. So, now we know that the cycling of carbon from fatty acids to glutamate occurs and under hypoxic conditions broadly associated with neurotrauma, that carbons from glutamate are recycled to fatty acids. This observation creates new excitement for understanding how carbons flow under various conditions from glucose to fatty acid to amino acids and back. While certainly questions remain as to the underlying benefits to the neurons with regard to various potential protective mechanisms, e.g., a shift in NADH to NAD+ or reduced glutamate toxicity, this discovery opens
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
Review
our eyes to a new potential mechanism that is critical in protecting neurons during traumatic events.
Acknowledgments The author is an editor of the Journal of Neurochemistry.
References Bazan N. G. (1970) Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim. Biophys. Acta 218, 1–10. Bazan N. G. (1971) Changes in free fatty acids of brain by drug-induced convulsions, electroshock and anesthesia. J. Neurochem. 18, 1379–1385. Brose S., Marquardt A. L. and Golovko M. Y. (2013) Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia. J. Neurochem. 129, 400–412. Chan P. H., Kerlan R. and Fishman R. A. (1983) Reductions of Γ-aminobutyric acid and glutamate uptake and (Na+, K+)-ATPase activity in brain slices and synaptosomes by arachidonic acid. J. Neurochem. 40, 309–316. Choi D. W., Maulucci-Gedde M. and Kriegstein A. R. (1987) Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368. Cunnane S. C., Menard C. R., Likhodii S. S., Brenna J. T. and Crawford M. A. (1999) Carbon recycling into de novo lipogenesis is a major pathway in neonatal metabolism of linoleate and a-linolenate. Prostaglandins Leukot. Essent. Fatty Acids 60, 387–392. Cunnane S. C., Trotti D. and Ryan M. A. (2000) Specific linoleate deficiency in the rat does not prevent substantial carbon recycling from [14C]linoleate into sterols. J. Lipid Res. 41, 1808–1811. DeMar J. C., Jr, Ma K., Chang L., Bell J. M. and Rapoport S. I. (2005) a-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid. J. Neurochem. 94, 1063–1076. Goldberg W. J., Kadingo R. M. and Barrett J. N. (1986) Effects of ischemia-like conditions on cultured neurons: protection by low Na+, Low Ca2+ solutions. J. Neurosci. 6, 3144–3151. Golovko M. Y. and Murphy E. J. (2006) Uptake and metabolism of plasma derived euricic acid by rat brain. J. Lipid Res. 47, 1289–1297. Golovko M. Y., Rosenberger T. A., Færgeman N. J., Feddersen S., Cole N. B., Pribill I., Berger J., Nussbaum R. L. and Murphy E. J. (2006) Acyl-CoA synthetase activity links wild-type but not mutant a-synuclein to brain arachidonate metabolism. Biochemistry 45, 6956–6966. Haun S. E., Murphy E. J., Bates C. M. and Horrocks L. A. (1992) Extracellular calcium is a mediator of astroglial injury during combined glucose-oxygen deprivation. Brain Res. 593, 45–50. Hirsch-Reinshagen V., Zhou S., Burgess B. L., Bernier L., McIsaac S. A., Chan J. Y., Tansley G. H., Cohn J. S., Hayden M. R. and
365
Wellington C. L. (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J. Biol. Chem. 279, 41197–41207. Ikeda M., Yoshida S., Busto R., Santiso M. and Ginsberg M. D. (1986) Polyphosphoinositides as a probable source of brain free fatty acids accumulated at the onset of ischemia. J. Neurochem. 47, 123–132. Lin T. N., Liu T. H., Xu J., Hsu C. Y. and Sun G. Y. (1991) Brain polyphosphoinositide metabolism during focal ischemia in rat cortex. Stroke 22, 495–498. Menard C. R., Goodman K. J., Corso T. N., Brenna J. T. and Cunnane S. C. (1998) Recycling of carbon into lipids synthesized de novo is a quantitatively important pathway of a-[U-13C] linolenate utilization in the developing rat brain. J. Neurochem. 71, 2151–2158. Miller J. C., Gnaedinger J. M. and Rapoport S. I. (1987) Utilization of plasma fatty acid in rat brain: distribution of [14C]palmitate between oxidative and synthetic pathways. J. Neurochem. 49, 1507–1514. Moore S. A., Yoder E., Murphy S., Dutton G. R. and Spector A. A. (1991) Astrocytes, not neurons produce docosahexaenoic acid (22:6 omega-3) and arachidonic acid (20:4 omega-6). J. Neurochem. 56, 518–524. Murphy C. C., Murphy E. J. and Golovko M. Y. (2008) Eurcic acid is differentially taken up and metabolized in rat liver and heart. Lipids 43, 391–400. Nieweg K., Schaller H. and Pfrieger F. W. (2009) Marked differences in cholesterol synthesis between neurons and glial cells from postnatal rats. J. Neurochem. 109, 125–134. Pfrieger F. W. and Ungerer N. (2011) Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371. Rhoads D. E., Kaplan M. A., Peterson N. A. and Raghupathy E. (1982) Effects of free fatty acids on synaptosomal amino acid uptake systems. J. Neurochem. 38, 1255–1260. Rothman S. (1984) Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J. Neurosci. 4, 1884–1891. Rothman S. M. and Olney J. W. (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19, 105–111. Sheaff Greiner R. C., Zhang Q., Goodman K. J. and Giussani D. A. (1996) Linoleate, a-linolenate, and docosahexaenoate recycling into saturated and monounsaturated fatty acids is a major pathway in pregnant or lactating adults and fetal or infant rhesus monkeys. J. Lipid Res. 37, 2675–2686. Volterra A., Trotti D., Cassutti P., Tromba C., Salvaggio A., Melcangi R. C. and Racagni G. (1992) High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes. J. Neurochem. 59, 600–606. Yoshida S., Ideda M., Busto R., Santiso M., Martinez E. and Ginsberg M. D. (1986) Cerebral phosphoinositide, triacylglycerol, and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J. Neurochem. 47, 744–757.
© 2014 International Society for Neurochemistry, J. Neurochem. (2014) 129, 363--365
