Advertisement
J. Lipid Res.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Originally published In Press as doi:10.1194/jlr.R700017-JLR200 on February 5, 2008

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
R700017-JLR200v1
49/5/939    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Green, J. T.
Right arrow Articles by Bazinet, R. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Green, J. T.
Right arrow Articles by Bazinet, R. P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Journal of Lipid Research, Vol. 49, 939-944, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Review

The emerging role of group VI calcium-independent phospholipase A2 in releasing docosahexaenoic acid from brain phospholipids

Joshua T. Green, Sarah K. Orr and Richard P. Bazinet1

Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 3E2, Canada

Published, JLR Papers in Press, February 5, 2008.

1 To whom correspondence should be addressed. e-mail: richard.bazinet{at}utoronto.ca


   ABSTRACT
TOP
 ABSTRACT
BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
Brain phospholipids are highly enriched in docosahexaenoic acid (DHA; 22:6n-3). Recent advances indicate that 22:6n-3 is released from brain phospholipids via the action of phospholipase A2 (PLA2) in response to several stimuli, including neurotransmission, where it then acts as a secondary messenger. Furthermore, it is now known that released 22:6n-3 is a substrate for several oxygenation enzymes whose products are potent signaling molecules. One emerging candidate PLA2 involved in the release of 22:6n-3 from brain phospholipids is the group VI calcium-independent phospholipase A2 (iPLA2). After a brief review of brain 22:6n-3 metabolism, cell culture and rodent studies facilitating the hypothesis that group VI iPLA2 releases 22:6n-3 from brain phospholipids are discussed. The identification of PLA2s involved in cleaving 22:6n-3 from brain phospholipids could lead to the development of novel therapeutics for brain disorders in which 22:6n-3 signaling is disordered.

Supplementary key words signaling • cyclooxygenase • lipoxygenase • docosanoid • neuroprotectin • uptake • turnover • kinetics • neuroinflammation • arachidonic acid

Abbreviations: 18:2n-6, linoleic acid; 20:4n-6, arachidonic acid; 22:6n-3, docosahexaenoic acid; cPLA2, cytosolic phospholipase A2; iPLA2, calcium-independent phospholipase A2; PLA2, phospholipase A2; sPLA2, secretory phospholipase A2


   BRAIN UPTAKE AND UTILIZATION OF DOCOSAHEXAENOIC ACID
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
The mammalian brain is particularly enriched with the PUFA docosahexaenoic acid (DHA; 22:6n-3) (1). Within the brain, 22:6n-3 helps maintain membrane fluidity (2), promotes cell survival (3–5), acts as a secondary messenger via coupling to neuroreceptors (6–8), and is converted, via oxygenation, to a variety of signaling molecules, some of which have potent anti-inflammatory properties (9, 10). Thus, it is not surprising that 22:6n-3 is important in neural development (11, 12) and has been implicated in a variety of neurological disorders, including stroke (13), Alzheimer's disease (14), and major depression (15).

The brain cannot synthesize n-3 PUFAs de novo; therefore, it must either take up preformed 22:6n-3 or desaturate and elongate one of its precursors. With regard to the latter, although brain cells and in particular astrocytes have the capacity to desaturate and elongate {alpha}-linolenic acid (18:3n-3) to 22:6n-3 (16), in vivo tracer studies suggest that brain desaturation/elongation is a relatively minor pathway (0.024 pmol/g brain/s) (17) compared with brain uptake of preformed 22:6n-3 (13–15 pmol/g brain/s) (17–19). Furthermore, unlike the liver, the brain does not upregulate its ability to desaturate and elongate 18:3n-3 to 22:6n-3 when dietary n-3 PUFAs are limited (20–22).

Plasma unesterified 22:6n-3 rapidly disassociates from albumin, passes through the blood-brain barrier, and enters the brain (Fig. 1 , step A) (23–25). Upon its entry, 22:6n-3 is activated by an acyl-CoA synthetase (26, 27). A small portion of the newly formed docosahexaenoyl-CoA is β-oxidized (28, 29), and the remainder is esterified via an acyl-CoA transferase to the sn-2 position of phospholipids. The 22:6n-3 that enters the brain and passes through the docosahexaenoyl-CoA pool is esterified into brain phospholipids at a rate of 13–15 pmol/g brain/s. This 22:6n-3 pool is predominantly esterified to ethanolamine (6–7 pmol/g brain/s) and choline glycerophospholipids (4–5 pmol/g brain/s) (28–31), and subsequent remodeling and de novo phospholipid synthesis likely explain its relative mass distribution within various phospholipid species (32). Phospholipid 22:6n-3 (sn-2 esterified) is then released by phospholipase A2 (PLA2) at a net rate of 102–131 pmol/g brain/s (29–31). A portion of the released 22:6n-3 is available for the synthesis of oxygenated derivatives via cyclooxygenase-2 (33) or a putative 15-lipoxygenase (34), whereas the remainder is activated by an acyl-CoA synthetase in which, again, a small portion of it is available for β-oxidation and the remainder is reesterified into the sn-2 position of brain phospholipids. Kinetic studies estimate that under basal conditions, ~90% of the 22:6n-3 that is released via PLA2 is reesterified into the sn-2 position of brain phospholipids (29–31), and the 10% that is lost is replaced by uptake from the plasma unesterified 22:6n-3 pool (35).


Figure 1
View larger version (42K):
[in this window]
[in a new window]

  		Fig. 1. Docosahexaenoic acid (DHA; 22:6n-3) rapidly disassociates from plasma albumin and passes through the blood-brain barrier (A) into the brain, where it is activated by an acyl-CoA synthetase (B). Upon its activation, a small proportion of 22:6n-3 can be β-oxidized (C), whereas the remainder is esterified to a 2-lysophospholipid via acyl-CoA transferase (D). In this model, group VI calcium-independent phospholipase A2 (iPLA2) releases 22:6n-3 from neural phospholipids (creating the 2-lysophospholipid) (E), where a portion can be converted to oxygenated derivatives (F) or activated by acyl-CoA synthetase (G). ATP, thrombin, and bradykinin are known activators of iPLA2. Although cholinergic (M1) and serotonergic (5-HT2A) receptor activation releases 22:6n-3 from neural phospholipids, the PLA2 isoform involved is not known. Plasma unesterified 22:6n-3 enters the brain and is esterified to a 2-lysophospholipid at a rate of 13–15 pmol/g brain/s. However, the net rate of 22:6n-3 esterification to brain phospholipids also includes recycled 22:6n-3, leading to a net rate of 22:6n-3 entry into phospholipids from the docosahexaenoyl-CoA pool (D) of 102–131 pmol/g brain/s, which at steady state approximates the rate of 22:6n-3 release from brain phospholipids (E). NPD1, neuroprotectin D1; RvD1, resolvin D1.

 

   BRAIN PLA2
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
To date, at least 22 genes that encode PLA2 proteins have been identified in mammals. PLA2s cleave fatty acids from the sn-2 position of glycerophospholipids, resulting in an unesterified "free fatty acid" and a 2-lysophospholipid. On a broad level, the mammalian PLA2 isoforms differ with respect to their tissue and cellular distribution, substrate specificities, and calcium requirements, and interested readers should consult other reviews for more details (36–41), including PLA2 nomenclature/classification (41, 42). The isoforms identified in the brain to date include groups IVA, IVB, and IVC calcium-dependent cytosolic phospholipase A2 (cPLA2), groups IIA, IIC, IIE, V, and X calcium-dependent secretory phospholipase A2 (sPLA2), and groups VIA and VIB calcium-independent phospholipase A2 (iPLA2) (43–49). It is worth noting that the mouse strains C57BL/6, 129/Sv, and B10.RIII have a naturally occurring missense mutation in the gene encoding for the group IIA sPLA2 (45, 50–52). As new proteins with PLA2-like activity are identified (53, 54) and specific antibodies and reagents are developed, it is possible that more isoforms will be detected within the brain. Another, yet to be cloned, PLA2 whose activity has been detected in the brain is the plasmalogen-selective PLA2 (55). This enzyme is capable of cleaving fatty acids from plasmanyl-ethanolamine, and because in the brain this glycerophospholipid is rich in 22:6n-3, it is possible that this enzyme may also play a role in 22:6n-3 release from brain phospholipids (39, 56).


   GROUP VI iPLA2: OVERVIEW
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
There are two distinct members of the iPLA2 family, group VIA iPLA2 and group VIB iPLA2. The 85–88 kDa group VIA iPLA2 was first isolated from macrophages in 1994 (57) and independently cloned by two laboratories in 1997 (58, 59), whereas the group VIB iPLA2 was cloned in 2000 (49). The group VIA iPLA2 shares several conserved regions at the C terminus but has very little homology at the N terminus with the group VIB iPLA2. The group VI iPLA2s do not require calcium for their activity but do use ATP for stabilization; they are stimulated by thrombin and bradykinin (40, 60) but inhibited by bromoenolactone (61). However, very little is known about the molecular/genetic regulation of group VI iPLA2, especially within the brain (62). Initial studies suggested a homeostatic role for group VI iPLA2 in regulating membrane turnover (for review, see Ref. 63). However, several studies have now shown that group VI iPLA2 plays an important role in signal transduction (for review, see Refs. 40, 64).

In the brain, the basal expression and activity of group VI iPLA2 is higher than that of other PLA2s (43, 65–67) and its protein expression decreases during aging (68). Whereas brain cPLA2 and sPLA2 are commonly thought to be selective for arachidonic acid (20:4n-6) release (64, 69–73), the specific activity of group VI iPLA2 using 1-palmitoyl 2-R-phosphatidylcholine when linoleic acid (18:2n-6), palmitic acid, oleic acid, or 20:4n-6 were esterified in the sn-2 position (R) was 10.0, 4.3, 3.0, and 2.0 µmol/min/mg protein, respectively (65). However, it is important to consider cellular localization and substrate availability when trying to determine in vivo selectivity. The net rate of release of 18:2n-6 from brain phospholipids (19 pmol/g brain/s) was at least five times lower than that of 22:6n-3 (102–131 pmol/g brain/s), and when preformed 22:6n-3 is present in chow, the concentration of phospholipid esterified 18:2n-6 (987 nmol/g brain) was almost 15 times lower than that of 22:6n-3 (13,844 nmol/g brain) (18). Although these latter observations do not suggest that group VI iPLA2 is not involved in cleaving 18:2n-6 from brain phospholipids, they do raise the question of why so much group VI iPLA2 is present in the brain when so little 18:2n-6 is present.


   GROUP VI iPLA2 AND 22:6n-3 RELEASE FROM BRAIN PHOSPHOLIPIDS
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
Evidence from cell culture studies
The first suggestion that brain group VI iPLA2 may be selective for 22:6n-3 release came from Strokin, Sergeeva, and Reiser (60) when they observed that bromoenolactone inhibited 22:6n-3 but not 20:4n-6 release from phospholipids of astrocytes stimulated with ATP. This study was followed up by showing that bromoenolactone also inhibited oxygen/glucose deprivation-induced 22:6n-3 release from hippocampal phospholipids (74). In 2007, Strokin, Sergeeva, and Reiser (48) repeated their 2003 finding in which ATP-stimulated 22:6n-3 release from astrocyte phospholipids was inhibited with bromoenolactone and reproduced this effect with small interfering RNA silencing of group VIB iPLA2. This latter study addressed the issue of bromoenolactone inhibition selectivity and was followed up by further demonstrating that bromoenolactone inhibition of 22:6n-3 release from astrocyte phospholipids was absent upon silencing group VIB iPLA2.

Evidence from in vivo studies
DeMar et al. (75) tested the half-life of [4,5-3H]22:6n-3 upon its intracerebroventricular administration to rats that had consumed a diet either adequate or deprived of n-3 PUFAs for 15 weeks postweaning. The half-life of [4,5-3H]22:6n-3 in brain phospholipids of rats consuming the n-3 PUFA-adequate diet was 33 days, whereas it was increased to 90 days in the deprived rats. This conservation of [4,5-3H]22:6n-3 suggested that enzymes involved in the catabolism of 22:6n-3 must be downregulated in the brains of n-3 PUFA-deprived rats, and in a subsequent experiment candidate brain PLA2 isoforms (IIA sPLA2, IVA cPLA2, and VIA iPLA2) were examined (47). Whereas the activity, protein, and mRNA of group IVA cPLA2 and group IIA sPLA2 were upregulated in the brains of rats consuming the n-3 PUFA-deprived diet, only the group VIA iPLA2 isoform was downregulated, making it a candidate mechanism by which the brain half-life of [4,5-3H]22:6n-3 was prolonged (47, 75). The activity, protein, and mRNA of group VIA iPLA2 were downregulated; however, the mechanism by which group VIA iPLA2 mRNA was downregulated was not explored, and whether or not there was a downregulation of group VIB iPLA2 was not tested.


   CONSEQUENCES OF 22:6n-3 RELEASE FROM BRAIN PHOSPHOLIPIDS
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
SUMMARY AND CONCLUSIONS
 REFERENCES
 
Although many important functions have been attributed to 22:6n-3 within the brain (2, 76–78), few studies have attempted to test whether these functions are related to released 22:6n-3. Rats deprived of dietary n-3 PUFAs to reduce brain concentrations have behavioral deficits (79, 80), altered neurotransmission (81, 82), decreased iPLA2 activity and expression (47), and decreased 22:6n-3 release from brain phospholipids (75, 83). A portion of released 22:6n-3 can be converted to neuroprotectin D1 or resolvin D1 (Fig. 1, step F), two signaling molecules involved in brain cell survival and the resolution of inflammation (10, 13, 84). Docosahexaenoyl-CoA is a hepatic nuclear factor-4{alpha} ligand (85), whereas unesterified 22:6n-3 is a peroxisome proliferator-activated receptor ligand (86). Unesterified 22:6n-3 inhibits protein kinase C activity (87) and has been implicated in the regulation of brain nuclear factor-{kappa}B (13), p38 mitogen-activated protein kinase (5), Bcl-2 (84), and Akt (88) signaling pathways. Furthermore, the activation of 22:6n-3 by acyl-CoA synthetase (102–131 pmol/g brain/s) requires the use of two high-energy phosphates from one ATP (22:6n-3 + CoA + ATP -> 22:6n-3-CoA + AMP + PPi; Fig. 1, step G), consuming ~0.1% of the rodent brain's 208 nmol/g brain/s ATP (89–91). Future studies are needed to determine the consequences of this energetically expensive 22:6n-3 release and reesterification.


   SUMMARY AND CONCLUSIONS
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
REFERENCES
 
Recent studies have identified 22:6n-3 as an important secondary messenger within the brain. The PLA2 isoform involved in 22:6n-3 release from neural phospholipids upon cholinergic (M1) (6, 8) and serotonergic (5-HT2A) (7, 92) stimulation is not known. Unesterified 22:6n-3 likely directly, as well as through its oxygenated derivatives, participates in signal transduction. Cell culture studies using small molecule inhibitors and small interfering RNAs as well as kinetic studies in the rodent brain suggest that group VI iPLA2 is involved in cleaving 22:6n-3 from brain phospholipids (Fig. 1). Future studies are needed to identify the specific roles of group VIA and VIB iPLA2 in 22:6n-3 release from brain phospholipids. Further approaches to answering these questions could include the study of sn-2 radiolabeled 22:6n-3 glycerophospholipids in group VI iPLA2-specific assay systems, the generation and characterization of groups VIA and VIB iPLA2 brain-specific knockouts, or the assessment of 22:6n-3 kinetics in other models with altered brain group VI iPLA2 activity. To date, it is known that group VIA iPLA2 decreases in the hippocampus in response to aging (68) and in the cortex in response to dietary n-3 PUFA deprivation (47). Whether or not decreased group VI iPLA2 and its potential ability to regulate 22:6n-3 release from brain phospholipids are contributing factors in the susceptibility of the aged or the n-3 PUFA-deprived brain to disease remains to be tested.


   ACKNOWLEDGMENTS
 
R.P.B. received funding from the Natural Sciences and Engineering Research Council of Canada.

Submitted on October 15, 2007
Revised on December 20, 2007


   REFERENCES
TOP
 ABSTRACT
 BRAIN UPTAKE AND UTILIZATION...
 BRAIN PLA2
 GROUP VI iPLA2: OVERVIEW
 GROUP VI iPLA2 AND...
 CONSEQUENCES OF 22:6n-3 RELEASE...
 SUMMARY AND CONCLUSIONS
 REFERENCES
 
  1. Diau, G. Y., A. T. Hsieh, E. A. Sarkadi-Nagy, V. Wijendran, P. W. Nathanielsz, and J. T. Brenna. 2005. The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system. BMC Med. 3: 11.[CrossRef][Medline]

  2. Salem, N., Jr., B. Litman, H. Y. Kim, and K. Gawrisch. 2001. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids. 36: 945–959.[Medline]

  3. Bazan, N. G. 2005. Lipid signaling in neural plasticity, brain repair, and neuroprotection. Mol. Neurobiol. 32: 89–103.[CrossRef][Medline]

  4. Kim, H. Y. 2007. Novel metabolism of docosahexaenoic acid in neural cells. J. Biol. Chem. 282: 18661–18665.[Free Full Text]

  5. Rao, J. S., R. N. Ertley, H. J. Lee, J. C. DeMar, Jr., J. T. Arnold, S. I. Rapoport, and R. P. Bazinet. 2007. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol. Psychiatry. 12: 36–46.[CrossRef][Medline]

  6. Jones, C. R., T. Arai, and S. I. Rapoport. 1997. Evidence for the involvement of docosahexaenoic acid in cholinergic stimulated signal transduction at the synapse. Neurochem. Res. 22: 663–670.[CrossRef][Medline]

  7. Garcia, M. C., and H. Y. Kim. 1997. Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Brain Res. 768: 43–48.[CrossRef][Medline]

  8. DeGeorge, J. J., T. Nariai, S. Yamazaki, W. M. Williams, and S. I. Rapoport. 1991. Arecoline-stimulated brain incorporation of intravenously administered fatty acids in unanesthetized rats. J. Neurochem. 56: 352–355.[CrossRef][Medline]

  9. Ariel, A., and C. N. Serhan. 2007. Resolvins and protectins in the termination program of acute inflammation. Trends Immunol. 28: 176–183.[CrossRef][Medline]

  10. Schwab, J. M., N. Chiang, M. Arita, and C. N. Serhan. 2007. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 447: 869–874.[CrossRef][Medline]

  11. Neuringer, M., W. E. Connor, D. S. Lin, L. Barstad, and S. Luck. 1986. Biochemical and functional effects of prenatal and postnatal omega 3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc. Natl. Acad. Sci. USA. 83: 4021–4025.[Abstract/Free Full Text]

  12. Gibson, R. A., and M. Makrides. 1998. The role of long chain polyunsaturated fatty acids (LCPUFA) in neonatal nutrition. Acta Paediatr. 87: 1017–1022.[CrossRef][Medline]

  13. Marcheselli, V. L., S. Hong, W. J. Lukiw, X. H. Tian, K. Gronert, A. Musto, M. Hardy, J. M. Gimenez, N. Chiang, C. N. Serhan, et al. 2003. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278: 43807–43817.[Abstract/Free Full Text]

  14. Calon, F., G. P. Lim, F. Yang, T. Morihara, B. Teter, O. Ubeda, P. Rostaing, A. Triller, N. Salem, Jr., K. H. Ashe, et al. 2004. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 43: 633–645.[CrossRef][Medline]

  15. Sinclair, A. J., D. Begg, M. Mathai, and R. S. Weisinger. 2007. Omega 3 fatty acids and the brain: review of studies in depression. Asia Pac. J. Clin. Nutr. 16(Suppl. 1): 391–397.[Medline]

  16. Williard, D. E., S. D. Harmon, T. L. Kaduce, M. Preuss, S. A. Moore, M. E. Robbins, and A. A. Spector. 2001. Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in differentiated rat brain astrocytes. J. Lipid Res. 42: 1368–1376.[Abstract/Free Full Text]

  17. DeMar, J. C., Jr., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2005. {alpha}-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.[CrossRef][Medline]

  18. DeMar, J. C., Jr., H. J. Lee, L. Chang, J. M. Bell, S. I. Rapoport, and R. P. Bazinet. 2006. Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats. Biochim. Biophys. Acta. 1761: 1050–1059.[Medline]

  19. Garattini, G., P. Crozzoli, and F. Brenna. 1999. Bilateral dental fusion of the upper central incisors: a multidisciplinary approach. J. Esthet. Dent. 11: 149–154.[CrossRef][Medline]

  20. Igarashi, M., J. C. DeMar, Jr., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2007. Upregulated liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet. J. Lipid Res. 48: 152–164.[Abstract/Free Full Text]

  21. Igarashi, M., J. C. DeMar, Jr., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2007. Docosahexaenoic acid synthesis from alpha-linolenic acid by rat brain is unaffected by dietary n-3 PUFA deprivation. J. Lipid Res. 48: 1150–1158.[Abstract/Free Full Text]

  22. Igarashi, M., K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2007. Dietary n-3 PUFA deprivation for 15 weeks upregulates elongase and desaturase expression in rat liver but not brain. J. Lipid Res. 48: 2463–2470.[Abstract/Free Full Text]

  23. Robinson, P. J., J. Noronha, J. J. DeGeorge, L. M. Freed, T. Nariai, and S. I. Rapoport. 1992. A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res. Brain Res. Rev. 17: 187–214.[CrossRef][Medline]

  24. Hamilton, J. A., and K. Brunaldi. 2007. A model for fatty acid transport into the brain. J. Mol. Neurosci. 33: 146–150.[CrossRef][Medline]

  25. Chen, C. T., D. W. Ma, J. H. Kim, H. T. Mount, and R. P. Bazinet. 2008. The low density lipoprotein receptor is not necessary for maintaining mouse brain polyunsaturated fatty acid concentrations. J. Lipid Res. 49: 147–152.[Abstract/Free Full Text]

  26. Bazinet, R. P., M. T. Weis, S. I. Rapoport, and T. A. Rosenberger. 2006. Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl.). 184: 122–129.[Medline]

  27. Mashek, D. G., L. O. Li, and R. A. Coleman. 2006. Rat long-chain acyl-CoA synthetase mRNA, protein, and activity vary in tissue distribution and in response to diet. J. Lipid Res. 47: 2004–2010.[Abstract/Free Full Text]

  28. Cunnane, S. C., M. A. Ryan, C. R. Nadeau, R. P. Bazinet, K. Musa-Veloso, and U. McCloy. 2003. Why is carbon from some polyunsaturates extensively recycled into lipid synthesis? Lipids. 38: 477–484.[CrossRef][Medline]

  29. Lee, H. J., S. Ghelardoni, L. Chang, F. Bosetti, S. I. Rapoport, and R. P. Bazinet. 2005. Topiramate does not alter the kinetics of arachidonic or docosahexaenoic acid in brain phospholipids of the unanesthetized rat. Neurochem. Res. 30: 677–683.[CrossRef][Medline]

  30. Bazinet, R. P., J. S. Rao, L. Chang, S. I. Rapoport, and H. J. Lee. 2005. Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl.). 182: 180–185.[CrossRef][Medline]

  31. Bazinet, R. P., J. S. Rao, L. Chang, S. I. Rapoport, and H. J. Lee. 2006. Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder. Biol. Psychiatry. 59: 401–407.[CrossRef][Medline]

  32. Kim, H. Y., J. Bigelow, and J. H. Kevala. 2004. Substrate preference in phosphatidylserine biosynthesis for docosahexaenoic acid containing species. Biochemistry. 43: 1030–1036.[CrossRef][Medline]

  33. Serhan, C. N., S. Hong, K. Gronert, S. P. Colgan, P. R. Devchand, G. Mirick, and R. L. Moussignac. 2002. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196: 1025–1037.[Abstract/Free Full Text]

  34. Serhan, C. N., and J. Savill. 2005. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6: 1191–1197.[CrossRef][Medline]

  35. Rapoport, S. I., J. S. Rao, and M. Igarashi. 2007. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins Leukot. Essent. Fatty Acids. 77: 251–261.[CrossRef][Medline]

  36. Ghosh, M., R. Loper, F. Ghomashchi, D. E. Tucker, J. V. Bonventre, M. H. Gelb, and C. C. Leslie. 2007. Function, activity, and membrane targeting of cytosolic phospholipase A(2)zeta in mouse lung fibroblasts. J. Biol. Chem. 282: 11676–11686.[Abstract/Free Full Text]

  37. Farooqui, A. A., W. Y. Ong, and L. A. Horrocks. 2006. Inhibitors of brain phospholipase A2 activity: their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders. Pharmacol. Rev. 58: 591–620.[Abstract/Free Full Text]

  38. Bonventre, J. V., and A. Sapirstein. 2002. Group IV cytosolic phospholipase A2 (PLA2) function: insights from the knockout mouse. Adv. Exp. Med. Biol. 507: 25–31.[Medline]

  39. Farooqui, A. A., and L. A. Horrocks. 2004. Brain phospholipases A2: a perspective on the history. Prostaglandins Leukot. Essent. Fatty Acids. 71: 161–169.[CrossRef][Medline]

  40. Balsinde, J., and M. A. Balboa. 2005. Cellular regulation and proposed biological functions of group VIA calcium-independent phospholipase A2 in activated cells. Cell. Signal. 17: 1052–1062.[CrossRef][Medline]

  41. Schaloske, R. H., and E. A. Dennis. 2006. The phospholipase A2 superfamily and its group numbering system. Biochim. Biophys. Acta. 1761: 1246–1259.[Medline]

  42. Six, D. A., and E. A. Dennis. 2000. The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochim. Biophys. Acta. 1488: 1–19.[Medline]

  43. Molloy, G. Y., M. Rattray, and R. J. Williams. 1998. Genes encoding multiple forms of phospholipase A2 are expressed in rat brain. Neurosci. Lett. 258: 139–142.[CrossRef][Medline]

  44. Pickard, R. T., B. A. Strifler, R. M. Kramer, and J. D. Sharp. 1999. Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2. J. Biol. Chem. 274: 8823–8831.[Abstract/Free Full Text]

  45. Hamaguchi, K., H. Kuwata, K. Yoshihara, S. Masuda, S. Shimbara, S.Oh-ishi, M. Murakami, and I. Kudo. 2003. Induction of distinct sets of secretory phospholipase A(2) in rodents during inflammation. Biochim. Biophys. Acta. 1635: 37–47.[Medline]

  46. Kolko, M., N. R. Christoffersen, S. G. Barreiro, M. L. Miller, A. J. Pizza, and N. G. Bazan. 2006. Characterization and location of secretory phospholipase A2 groups IIE, V, and X in the rat brain. J. Neurosci. Res. 83: 874–882.[CrossRef]

  47. Rao, J. S., R. N. Ertley, J. C. DeMar, Jr., S. I. Rapoport, R. P. Bazinet, and H. J. Lee. 2007. Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol. Psychiatry. 12: 151–157.[CrossRef][Medline]

  48. Strokin, M., M. Sergeeva, and G. Reiser. 2007. Prostaglandin synthesis in rat brain astrocytes is under the control of the n-3 docosahexaenoic acid, released by group VIB calcium-independent phospholipase A(2). J. Neurochem. 102: 1771–1782.[CrossRef][Medline]

  49. Mancuso, D. J., C. M. Jenkins, and R. W. Gross. 2000. The genomic organization, complete mRNA sequence, cloning, and expression of a novel human intracellular membrane-associated calcium-independent phospholipase A(2). J. Biol. Chem. 275: 9937–9945.[Abstract/Free Full Text]

  50. Sapirstein, A., and J. V. Bonventre. 2000. Specific physiological roles of cytosolic phospholipase A(2) as defined by gene knockouts. Biochim. Biophys. Acta. 1488: 139–148.[Medline]

  51. Bosetti, F. 2007. Arachidonic acid metabolism in brain physiology and pathology: lessons from genetically altered mouse models. J. Neurochem. 102: 577–586.[CrossRef][Medline]

  52. Kennedy, B. P., P. Payette, J. Mudgett, P. Vadas, W. Pruzanski, M. Kwan, C. Tang, D. E. Rancourt, and W. A. Cromlish. 1995. A natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J. Biol. Chem. 270: 22378–22385.[Abstract/Free Full Text]

  53. Jenkins, C. M., D. J. Mancuso, W. Yan, H. F. Sims, B. Gibson, and R. W. Gross. 2004. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 279: 48968–48975.[Abstract/Free Full Text]

  54. Manevich, Y., K. S. Reddy, T. Shuvaeva, S. Feinstein, and A. Fisher. 2007. Structure and phospholipase function of peroxiredoxin 6: identification of the catalytic triad and its role in phospholipid substrate binding. J. Lipid Res. 48: 2306–2318.[Abstract/Free Full Text]

  55. Hirashima, Y., A. A. Farooqui, J. S. Mills, and L. A. Horrocks. 1992. Identification and purification of calcium-independent phospholipase A2 from bovine brain cytosol. J. Neurochem. 59: 708–714.[Medline]

  56. Farooqui, A. A., L. A. Horrocks, and T. Farooqui. 2007. Modulation of inflammation in brain: a matter of fat. J. Neurochem. 101: 577–599.[CrossRef][Medline]

  57. Ackermann, E. J., E. S. Kempner, and E. A. Dennis. 1994. Ca(2+)-independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J. Biol. Chem. 269: 9227–9233.[Abstract/Free Full Text]

  58. Balboa, M. A., J. Balsinde, S. S. Jones, and E. A. Dennis. 1997. Identity between the Ca2+-independent phospholipase A2 enzymes from P388D1 macrophages and Chinese hamster ovary cells. J. Biol. Chem. 272: 8576–8580.[Abstract/Free Full Text]

  59. Tang, J., R. W. Kriz, N. Wolfman, M. Shaffer, J. Seehra, and S. S. Jones. 1997. A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs. J. Biol. Chem. 272: 8567–8575.[Abstract/Free Full Text]

  60. Strokin, M., M. Sergeeva, and G. Reiser. 2003. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br. J. Pharmacol. 139: 1014–1022.[CrossRef][Medline]

  61. Ackermann, E. J., K. Conde-Frieboes, and E. A. Dennis. 1995. Inhibition of macrophage Ca(2+)-independent phospholipase A2 by bromoenol lactone and trifluoromethyl ketones. J. Biol. Chem. 270: 445–450.[Abstract/Free Full Text]

  62. Chakraborti, S. 2003. Phospholipase A(2) isoforms: a perspective. Cell. Signal. 15: 637–665.[CrossRef][Medline]

  63. Winstead, M. V., J. Balsinde, and E. A. Dennis. 2000. Calcium-independent phospholipase A(2): structure and function. Biochim. Biophys. Acta. 1488: 28–39.[Medline]

  64. Leslie, C. C. 2004. Regulation of arachidonic acid availability for eicosanoid production. Biochem. Cell Biol. 82: 1–17.[CrossRef][Medline]

  65. Yang, H. C., M. Mosior, B. Ni, and E. A. Dennis. 1999. Regional distribution, ontogeny, purification, and characterization of the Ca2+-independent phospholipase A2 from rat brain. J. Neurochem. 73: 1278–1287.[CrossRef][Medline]

  66. Yang, H. C., M. Mosior, C. A. Johnson, Y. Chen, and E. A. Dennis. 1999. Group-specific assays that distinguish between the four major types of mammalian phospholipase A2. Anal. Biochem. 269: 278–288.[CrossRef][Medline]

  67. Lee, H. J., J. S. Rao, R. N. Ertley, L. Chang, S. I. Rapoport, and R. P. Bazinet. 2006. Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl.). 190: 103–115.[CrossRef]

  68. Aid, S., and F. Bosetti. 2007. Gene expression of cyclooxygenase-1 and Ca(2+)-independent phospholipase A(2) is altered in rat hippocampus during normal aging. Brain Res. Bull. 73: 108–113.[CrossRef][Medline]

  69. Alonso, F., P. M. Henson, and C. C. Leslie. 1986. A cytosolic phospholipase in human neutrophils that hydrolyzes arachidonoyl-containing phosphatidylcholine. Biochim. Biophys. Acta. 878: 273–280.[Medline]

  70. Farooqui, A. A., L. A. Horrocks, and T. Farooqui. 2000. Deacylation and reacylation of neural membrane glycerophospholipids. J. Mol. Neurosci. 14: 123–135.[CrossRef][Medline]

  71. Rapoport, S. I., and F. Bosetti. 2002. Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch. Gen. Psychiatry. 59: 592–596.[Abstract/Free Full Text]

  72. Lee, H. J., J. S. Rao, S. I. Rapoport, and R. P. Bazinet. 2007. Antimanic therapies target brain arachidonic acid signaling: lessons learned about the regulation of brain fatty acid metabolism. Prostaglandins Leukot. Essent. Fatty Acids. 77: 239–246.[CrossRef][Medline]

  73. Leslie, C. C. 2004. Regulation of the specific release of arachidonic acid by cytosolic phospholipase A2. Prostaglandins Leukot. Essent. Fatty Acids. 70: 373–376.[CrossRef][Medline]

  74. Strokin, M., O. Chechneva, K. G. Reymann, and G. Reiser. 2006. Neuroprotection of rat hippocampal slices exposed to oxygen-glucose deprivation by enrichment with docosahexaenoic acid and by inhibition of hydrolysis of docosahexaenoic acid-containing phospholipids by calcium independent phospholipase A2. Neuroscience. 140: 547–553.[CrossRef][Medline]

  75. DeMar, J. C., Jr., K. Ma, J. M. Bell, and S. I. Rapoport. 2004. Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. J. Neurochem. 91: 1125–1137.[CrossRef][Medline]

  76. Heird, W. C., and A. Lapillonne. 2005. The role of essential fatty acids in development. Annu. Rev. Nutr. 25: 549–571.[CrossRef][Medline]

  77. Freemantle, E., M. Vandal, J. Tremblay-Mercier, S. Tremblay, J. C. Blachere, M. E. Begin, J. T. Brenna, A. Windust, and S. C. Cunnane. 2006. Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot. Essent. Fatty Acids. 75: 213–220.[CrossRef][Medline]

  78. Calon, F., and G. Cole. 2007. Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: evidence from animal studies. Prostaglandins Leukot. Essent. Fatty Acids. 77: 287–293.[CrossRef][Medline]

  79. Moriguchi, T., R. S. Greiner, and N. Salem, Jr. 2000. Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J. Neurochem. 75: 2563–2573.[CrossRef][Medline]

  80. DeMar, J. C., Jr., K. Ma, J. M. Bell, M. Igarashi, D. Greenstein, and S. I. Rapoport. 2006. One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J. Lipid Res. 47: 172–180.[Abstract/Free Full Text]

  81. Aid, S., S. Vancassel, A. Linard, M. Lavialle, and P. Guesnet. 2005. Dietary docosahexaenoic acid [22:6(n-3)] as a phospholipid or a triglyceride enhances the potassium chloride-evoked release of acetylcholine in rat hippocampus. J. Nutr. 135: 1008–1013.[Abstract/Free Full Text]

  82. Aid, S., S. Vancassel, C. Poumes-Ballihaut, S. Chalon, P. Guesnet, and M. Lavialle. 2003. Effect of a diet-induced n-3 PUFA depletion on cholinergic parameters in the rat hippocampus. J. Lipid Res. 44: 1545–1551.[Abstract/Free Full Text]

  83. Contreras, M. A., R. S. Greiner, M. C. Chang, C. S. Myers, N. Salem, Jr., and S. I. Rapoport. 2000. Nutritional deprivation of alpha-linolenic acid decreases but does not abolish turnover and availability of unacylated docosahexaenoic acid and docosahexaenoyl-CoA in rat brain. J. Neurochem. 75: 2392–2400.[CrossRef][Medline]

  84. Lukiw, W. J., J. G. Cui, V. L. Marcheselli, M. Bodker, A. Botkjaer, K. Gotlinger, C. N. Serhan, and N. G. Bazan. 2005. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115: 2774–2783.[CrossRef][Medline]

  85. Hertz, R., J. Magenheim, I. Berman, and J. Bar-Tana. 1998. Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature. 392: 512–516.[CrossRef][Medline]

  86. Keller, H., C. Dreyer, J. Medin, A. Mahfoudi, K. Ozato, and W. Wahli. 1993. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc. Natl. Acad. Sci. USA. 90: 2160–2164.[Abstract/Free Full Text]

  87. Seung Kim, H. F., E. J. Weeber, J. D. Sweatt, A. L. Stoll, and L. B. Marangell. 2001. Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro. Mol. Psychiatry. 6: 246–248.[CrossRef][Medline]

  88. Akbar, M., F. Calderon, Z. Wen, and H. Y. Kim. 2005. Docosahexaenoic acid: a positive modulator of Akt signaling in neuronal survival. Proc. Natl. Acad. Sci. USA. 102: 10858–10863.[Abstract/Free Full Text]

  89. Purdon, A. D., T. A. Rosenberger, H. U. Shetty, and S. I. Rapoport. 2002. Energy consumption by phospholipid metabolism in mammalian brain. Neurochem. Res. 27: 1641–1647.[CrossRef][Medline]

  90. Hisanaga, Y., H. Ago, N. Nakagawa, K. Hamada, K. Ida, M. Yamamoto, T. Hori, Y. Arii, M. Sugahara, S. Kuramitsu, et al. 2004. Structural basis of the substrate-specific two-step catalysis of long chain fatty acyl-CoA synthetase dimer. J. Biol. Chem. 279: 31717–31726.[Abstract/Free Full Text]

  91. Purdon, A. D., and S. I. Rapoport. 2007. Energy consumption by phospholipid metabolism in mammalian brain. In Neural Energy Utilization: Handbook of Neurochemistry and Molecular Biology. 3rd edition. Springer, New York. 401–427.

  92. Garcia, M. C., K. Y. Kim, C. Hough, and H. Y. Kim. 1997. Effects of chronic ethanol on the mobilization of arachidonate and docosahexaenoate stimulated by the type 2A serotonin receptor agonist (+/–)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in C6 glioma cells. Alcohol. Clin. Exp. Res. 21: 1465–1470.[Medline]


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
J. T. Green, Z. Liu, and R. P. Bazinet
Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived diet
J. Lipid Res., March 1, 2010; 51(3): 535 - 543.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. J. Mancuso, P. Kotzbauer, D. F. Wozniak, H. F. Sims, C. M. Jenkins, S. Guan, X. Han, K. Yang, G. Sun, I. Malik, et al.
Genetic Ablation of Calcium-independent Phospholipase A2{gamma} Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction
J. Biol. Chem., December 18, 2009; 284(51): 35632 - 35644.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
J. C. Umhau, W. Zhou, R. E. Carson, S. I. Rapoport, A. Polozova, J. Demar, N. Hussein, A. K. Bhattacharjee, K. Ma, G. Esposito, et al.
Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography
J. Lipid Res., July 1, 2009; 50(7): 1259 - 1268.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
R700017-JLR200v1
49/5/939    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Green, J. T.
Right arrow Articles by Bazinet, R. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Green, J. T.
Right arrow Articles by Bazinet, R. P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Journal of Biological Chemistry 
 Molecular and Cellular Proteomics   ASBMB Today 
Advertisement
spacer
Advertisement
Advertisement