Biological Effects of Lysophosphatidic Acid in the Nervous System

doi:10.1016/B978-0-12-394307-1.00005-9

International Review of Cell and Molecular Biology

Volume 296, 2012, Pages 273-322

https://doi.org/10.1016/B978-0-12-394307-1.00005-9 Get rights and content

Abstract

Lysophosphatidic acid (LPA) is a bioactive lipid that regulates a broad range of cellular effects in various cell types, leading to a variety of responses in tissues, including in the nervous system. LPA and its receptors are found in the nervous system, with different cellular and temporal profiles. Through its ability to target most cells of the nervous system and its induction of pleiotropic effects, LPA mediates events during neural development and adulthood. In this review, we summarize the current knowledge on the effects of LPA in the nervous system, during development and adulthood, and in various pathologies of the nervous system. We also explore potential LPA intervention strategies for anti-LPA therapeutics.

Introduction

Lipids and their derivatives are essential macromolecules that used to be merely seen as suppliers of energy and as structural cell membrane support. Based on homology of their structure, lipids can be categorized into several groups including phospholipids. There are two main types of phospholipids, glycerophospholipids, which are derived from glycerol, and sphingolipids, which are derived from sphingosine. Aside from their energy and structural functions, a few members of the lipid family are bioactive and induce specific biological effects in various cell types through binding to their specific membrane receptors.

Lysophosphatidic acid (LPA) is a glycerophospholipid that regulates a broad range of cellular responses, including cell growth, migration, and morphology, and it has been shown to play a major role in development. LPA is also an inflammatory and wound-healing mediator that is released from activated platelets and other players in the inflammatory process, including the production of various proinflammatory cytokines. LPA and its receptors are found in the central nervous system (CNS), and LPA has been shown to play a role in CNS development and pathology. This review aims at describing the current knowledge on the effects of LPA in the nervous system, during development, adulthood, and various neuropathologies.

Section snippets

LPA metabolism and catabolism

LPA is not a single molecular entity but a collection of structural analogs with a single functional glycerol alcohol phosphate moiety esterified to a variety of fatty acyl hydrocarbons of varied lengths and degrees of saturation. Detectable levels of LPA have been found in various body fluids, including serum, plasma, saliva, follicular fluid, inflammatory fluids, some malignant effusions, and cerebrospinal fluid (reviewed in Aoki et al., 2008). A broad range of cell types are known to produce

LPA Receptor Expression in the Developing and Adult Nervous System

Various studies have informed on the pattern of expression of LPA receptors in the nervous system and globally indicate that LPA receptors are mainly expressed during development and decrease in adulthood. An elegant study by Ohuchi et al. (2008) described the expression pattern of LPA_1–5 by whole-mount in situ hybridization in mouse embryos, confirming and further characterizing the expression profile of LPA receptors in the embryonic and postnatal mouse brain (Ohuchi et al., 2008). These

Neural stem/progenitor cells and neuroblasts

Neural stem cells can differentiate into either neural or neuronal progenitor cells. The neural progenitors are themselves able to differentiate into neurons, astrocytes, and oligodendrocytes while the neuronal progenitor cells, or neuroblasts, can only differentiate into neurons. In the CNS, NS/PCs are found in areas of neurogenesis during development (such as the ventricular zone) as well as in adulthood (such as the subventricular zone, the hippocampus, and potentially the spinal cord). LPA

Development

Atx is found in the floor plate and in the neural tube and then expressed during embryonic development and throughout postnatal life in the spinal cord, cerebellum, optic nerve, and the subventricular zone (Savaskan et al., 2007). Further, the Atx^(−/−) in mice is lethal due to the impairment of blood vessel and neural tube formation, while deletion of Atx in mice embryo is accompanied with perturbations in the closure of the neural tube closure and with aberrant neurite outgrowth (Fotopoulou et

Therapeutic Intervention

It is clear from the forgoing review of the literature that the LPA signaling system is quite extensive in the nervous system. LPA itself, its receptors, and the biosynthetic pathways for LPA generation are all present in important areas of the CNS including the hippocampus, subventricular zone, and DRG, and LPA receptors are expressed by all relevant cell types in the central and peripheral nervous systems. LPA is an important growth factor for CNS development, as its absence in the Atx

Concluding Remarks

As described in this review, LPA induces complex effects on all cell types of the nervous system. Not surprisingly, such pleiotropic effects are observed in development as well as in the adult. Studies also indicate important roles of LPA in the nervous system pathology. Development of new tools to access its signaling will undoubtedly give new insight into LPA's mechanisms of actions and provide novel potential therapeutical avenues.

Acknowledgments

This project is proudly supported by the Transport Accident Commission (A. P.). A. P. received a National Health and Medical Research Council Career Development Award. F. F. received an Australian Development Scholarships (ADS) by the Australian government (AusAID).

References (243)

N. Aaltonen et al.
Quantification of lysophosphatidic acids in rat brain tissue by liquid chromatography-electrospray tandem mass spectrometry
J. Chromatogr. B
(2010)
K. Abe et al.
Amyloid beta protein inhibits cellular MTT reduction not by suppression of mitochondrial succinate dehydrogenase but by acceleration of MTT formazan exocytosis in cultured rat cortical astrocytes
Neurosci. Res.
(1998)
S. An et al.
Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid
Biochem. Biophys. Res. Commun.
(1997)
S. An et al.
Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid
J. Biol. Chem.
(1998)
J. Aoki et al.
Two pathways for lysophosphatidic acid production
Biochim. Biophys. Acta
(2008)
D.L. Baker et al.
Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry
Anal. Biochem.
(2001)
K. Bandoh et al.
Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid
J. Biol. Chem.
(1999)
C. Bouquet et al.
MAP1B coordinates microtubule and actin filament remodeling in adult mouse Schwann cell tips and DRG neuron growth cones
Mol. Cell. Neurosci.
(2007)
N.A. Bowden et al.
Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia
Schizophr. Res.
(2006)
D.S. Campbell et al.
Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation
Neuron
(2001)

E. Castilla-Ortega et al.

Exploratory, anxiety and spatial memory impairments are dissociated in mice lacking the LPA1 receptor

Neurobiol. Learn. Mem.

(2010)

Y.-J. Chang et al.

Dioleoyl phosphatidic acid increases intracellular Ca2 + through endogenous LPA receptors in C6 glioma and L2071 fibroblasts

Prostaglandins Other Lipid Mediat.

(2007)

J. Chun et al.

Clonal cell lines produced by infection of neocortical neuroblasts using multiple oncogenes transduced by retroviruses

Mol. Cell. Neurosci.

(1996)

J.J. Contos et al.

The mouse lp(A3)/Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern

Gene

(2001)

P. Dash et al.

A role for hippocampal Rho-ROCK pathway in long-term spatial memory

Biochem. Biophys. Res. Commun.

(2004)

L. Desbonnet et al.

Mice mutant for genes associated with schizophrenia: common phenotype or distinct endophenotypes?

Behav. Brain Res.

(2009)

L. Dircks et al.

Acyltransferases of de novo glycerophospholipid biosynthesis

Prog. Lipid Res.

(1999)

S.J. Elmes et al.

Evidence for biological effects of exogenous LPA on rat primary afferent and spinal cord neurons

Brain Res.

(2004)

L.R. Fitzgerald et al.

Identification of an EDG7 variant, HOFNH30, a G-protein-coupled receptor for lysophosphatidic acid

Biochem. Biophys. Res. Commun.

(2000)

S. Fotopoulou et al.

ATX expression and LPA signalling are vital for the development of the nervous system

Dev. Biol.

(2010)

O. Fourcade et al.

Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells

Cell

(1995)

R. Fujita et al.

LPA-mediated demyelination in ex vivo culture of dorsal root

Neurochem. Int.

(2007)

K. Fukami et al.

Phosphatidic acid that accumulates in platelet-derived growth factor-stimulated Balb/c 3T3 cells is a potential mitogenic signal

J. Biol. Chem.

(1992)

N. Fukushima et al.

Actomyosin-dependent microtubule rearrangement in lysophosphatidic acid-induced neurite remodeling of young cortical neurons

Brain Res.

(2006)

N. Fukushima et al.

Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphology

Dev. Biol.

(2000)

N. Fukushima et al.

Lysophosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons

Mol. Cell. Neurosci.

(2002)

N. Fukushima et al.

Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-Gi/o pathway

Neurochem. Int.

(2007)

N. Fukushima et al.

Coordinated interactions between actin and microtubules through crosslinkers in neurite retraction induced by lysophosphatidic acid

Neurochem. Int.

(2011)

L. Gan et al.

Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

Biochem. Biophys. Res. Commun.

(2011)

W. Gattaz et al.

Increased PLA(2) activity in the hippocampus of patients with temporal lobe epilepsy and psychosis

J. Psychiatr. Res.

(2011)

M. Gotoh et al.

Effects of cyclic phosphatidic acid on delayed neuronal death following transient ischemia in rat hippocampal CA1

Eur. J. Pharmacol.

(2010)

S.M. Harrison et al.

LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease

Mol. Cell. Neurosci.

(2003)

M. Hernandez et al.

Secretory phospholipase A2 activates the cascade of mitogen-activated protein kinases and cytosolic phospholipase A2 in the human astrocytoma cell line 1321N1

J. Biol. Chem.

(1998)

M. Inoue et al.

Lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid

Neuroscience

(2008)

A.M. Abu El-Asrar et al.

Expression of autotaxin and acylglycerol kinase in proliferative vitreoretinal epiretinal membranes

Acta Ophthalmol.

(2011)

R. Adibhatla et al.

Altered lipid metabolism in brain injury and disorders

Subcell. Biochem.

(2008)

J. Allard et al.

A rat G protein-coupled receptor selectively expressed in myelin-forming cells

Eur. J. Neurosci.

(1998)

J. Allard et al.

Edg-2 in myelin-forming cells: isoforms, genomic mapping, and exclusion in Charcot-Marie-Tooth disease

Glia

(1999)

B. Annabi et al.

Modulation of invasive properties of CD133(+) glioblastoma stem cells: a role for MT1-MMP in bioactive lysophospholipid signaling

Mol. Carcinog.

(2009)

J.K. Atwal et al.

A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo

Sci. Transl. Med.

(2011)

S.C. Barber et al.

S1P and LPA trigger Schwann cell actin changes and migration

Eur. J. Neurosci.

(2004)

M.S. Beer et al.

EDG receptors as a therapeutic target in the nervous system

Ann. N. Y. Acad. Sci.

(2000)

M. Bektas et al.

A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells

J. Cell Biol.

(2005)

E. Bernhart et al.

Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

Proteomics

(2010)

E. Blanco et al.

Attenuation of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking LPA1 receptors

Psychopharmacology (Berl)

(2011)

N. Blondeau et al.

A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures

J. Cereb. Blood Flow Metab.

(2002)

A. Blum et al.

Rho-family GTPases modulate Ca(2 +)-dependent ATP release from astrocytes

Am. J. Physiol. Cell Physiol.

(2008)

D. Braff

Prepulse inhibition of the startle reflex: a window on the brain in schizophrenia

Curr. Top. Behav. Neurosci.

(2010)

S. Brault et al.

Lysophosphatidic acid induces endothelial cell death by modulating the redox environment

Am. J. Physiol.

(2007)

M. Casado et al.

Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: common features with mechanosensitivity

J. Physiol.

(1998)

Cited by (36)

Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylopic acid in a bioinspired lipoprotein nanoformulation
2021, Biomaterials
Citation Excerpt :
These two serve as intermediates in the synthesis of other classes of glycerophospholipids. For instance, under varying pathological/physiological conditions, and under the catalytic influence of phospholipase D and phospholipase A2, corresponding lysophospholipids (i.e. lysoPC and lysoPE) are formed [41]. The lysoPCs are known to be potent pro-inflammatory lipids, which under basal conditions exist in high concentrations albeit as albumin- or lipoprotein-bound forms while the lysoPEs are reported to elicit anti-inflammatory effects [42–44].
Xylopic acid (XA), a diterpene kaurene and the major active ingredient of the African spice Xylopia aethiopica (Annonaceae), is reported to possess anti-inflammatory and analgesic properties. Here, we investigated the therapeutic potential of XA for rheumatoid arthritis (RA), a debilitating autoimmune inflammatory disease characterized by joint damage, in the complete Freund's adjuvant (CFA)-induced arthritis model in rats. We synthesized bioinspired reconstituted high-density lipoprotein (rHDL) nanoparticles loaded with purified XA crystals (rHDL/XA) that passively accumulate in inflamed joints of CFA-induced arthritic rats. Treatment with rHDL/XA minimized mononuclear cell infiltration of CFA-induced arthritic sites and ameliorated disease burden. Metabolomic and transcriptomic analyses revealed that the major molecular pathways perturbed following CFA-induced arthritis correlated with amino acid and lipid metabolism, which were restored to normal states by rHDL/XA treatment. This work demonstrates the anti-RA potential of XA in a nanoformulation and uncovers its underlying therapeutic mechanisms at the transcript and metabolite levels.
Homer1/mGluR1-mediated ER stress contributes to lysophosphatidic acid-induced neurotoxicity in cortical neurons
2019, Neurochemistry International
Lysophosphatidic acid (LPA) is a glycerophospholipid that can be detected in serum, saliva and cerebrospinal fluid. However, the effect of LPA on neuronal death and survival has not been fully determined. In the present study, we investigated the potential neurotoxic effect of LPA in primary cultured cortical neurons. Treatment with LPA (0.5, 1 and 5 μM) markedly decreased neuronal viability, increased lactate dehydrogenase (LDH) release and promoted apoptosis in cortical neurons. The results of western blot showed that LPA increased the expression of endoplasmic reticulum (ER) stress associated factors, and the protein misfolding inhibitor 4-phenylbutyric acid (4-PBA) attenuated LPA-induced toxicity. In addition, treatment with LPA did not alter the expression and distribution of Homer1 in cortical neurons. The protein levels of metabotropic glutamate receptor 1 (mGluR1), but not metabotropic glutamate receptor 5 (mGluR5), were significantly increased by LPA at 12 and 24 h after treatment. Knockdown of Homer1 using specific siRNA partially prevented the LPA-induced neurotoxicity and ER stress. Furthermore, the results of Ca²⁺ imaging showed that treatment with LPA induced intracellular Ca²⁺ release, which could be partially prevented by 4-PBA and downregulation of Homer1. The LPA-induced intracellular Ca²⁺ release was associated with ER Ca²⁺ release through the Homer1-mGluR1 pathway. In summary, our results showed that LPA treatment induced ER stress and apoptosis in cortical neurons, and its neurotoxicity was partially mediated by Ca²⁺ release from the ER via the Homer1/mGluR1 pathway.
Metabolic perturbations after pediatric TBI: It's not just about glucose
2019, Experimental Neurology
Improved patient survival following pediatric traumatic brain injury (TBI) has uncovered a currently limited understanding of both the adaptive and maladaptive metabolic perturbations that occur during the acute and long-term phases of recovery. While much is known about the redundancy of metabolic pathways that provide adequate energy and substrates for normal brain growth and development, the field is only beginning to characterize perturbations in these metabolic pathways after pediatric TBI. To date, the majority of studies have focused on dysregulated oxidative glucose metabolism after injury; however, the immature brain is well-equipped to use alternative substrates to fuel energy production, growth, and development. A comprehensive understanding of metabolic changes associated with pediatric TBI cannot be limited to investigations of glucose metabolism alone. All energy substrates used by the brain should be considered in developing nutritional and pharmacological interventions for pediatric head trauma. This review summarizes post-injury changes in brain metabolism of glucose, lipids, ketone bodies, and amino acids with discussion of the therapeutic potential of altering substrate utilization to improve pediatric TBI outcomes.
Lysophosphatidic acid levels in cerebrospinal fluid and plasma samples in patients with major depressive disorder
2019, Heliyon
Major depressive disorder (MDD) is the most common psychiatric disorders. However, a biochemical marker has yet to be established for clinical purposes. It is proposed that lysophosphatidic acid (LPA, 1-acyl-2-sn-glycerol-3-phosphoate) plays some important roles in emotional regulation of experimental animals. Therefore, in this study, we measured LPA levels using enzyme-linked immunosorbent assays of cerebrospinal fluid (CSF) and plasma samples from patients with MDD. The participants were 52 patients and 49 normal healthy controls for CSF study, and 47 patients and 44 controls for plasma study. We used the Japanese version of the GRID Hamilton Depression Rating Scale (17-item version) for the assessment of depressive symptoms. We found no associations between LPA levels (CSF or plasma) and either diagnosis or severity of MDD, or with psychotropic medication. In conclusion, our data suggest that LPA levels likely would not serve as a practical biomarker of MDD.
Levels of lysophosphatidic acid in cerebrospinal fluid and plasma of patients with schizophrenia
2019, Psychiatry Research
It is suggested that lysophosphatidic acid (LPA) plays a key role in the pathophysiology of schizophrenia. In this study, we measured LPA levels by enzyme-linked immunosorbent assay in cerebrospinal fluid (CSF) and plasma samples. The participants were 49 patients with schizophrenia and 49 normal healthy controls for CSF study, and 42 patients and 44 controls for plasma study. We found that LPA levels in the patients were not significantly different from those of controls in CSF (controls: 0.189 ± 0.077 µM, patients: 0.175 ± 0.067 µM; P = 0.318) and plasma samples (controls: 0.131 ± 0.067 µM, patients: 0.120 ± 0.075 µM; P = 0.465). On the other hand, CSF levels in medicated patients (0.162 ± 0.061 µM) were significantly lower than those observed in unmedicated patients (0.224 ± 0.067 µM, P = 0.038), suggesting that our findings could be masked by the influence of medication with antipsychotics. Interestingly, we detected significant negative correlation between PANSS scores and plasma LPA levels, especially in males and in unmedicated patients. Our result suggests that LPA levels in CSF and plasma samples would not serve as a diagnostic biomarker, but plasma levels could be used for symptomatic assessment of schizophrenia.
Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology
2018, Progress in Lipid Research
Stem cells are unique in their ability to self-renew and differentiate into various cell types. Because of these features, stem cells are key to the formation of organisms and play fundamental roles in tissue regeneration and repair. Mechanisms controlling their fate are thus fundamental to the development and homeostasis of tissues and organs. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that play a wide range of roles in multiple cell types, during developmental and pathophysiological events. Considerable evidence now demonstrates the potent roles of LPA and S1P in the biology of pluripotent and adult stem cells, from maintenance to repair. Here we review their roles for each main category of stem cells and explore how those effects impact development and physiopathology.

View all citing articles on Scopus

View full text

Chapter five - Biological Effects of Lysophosphatidic Acid in the Nervous System

Abstract

Introduction

Section snippets

LPA metabolism and catabolism

LPA Receptor Expression in the Developing and Adult Nervous System

Neural stem/progenitor cells and neuroblasts

Development

Therapeutic Intervention

Concluding Remarks

Acknowledgments

J. Chromatogr. B

Neurosci. Res.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Biochim. Biophys. Acta

Anal. Biochem.

J. Biol. Chem.

Mol. Cell. Neurosci.

Schizophr. Res.

Neuron

Neurobiol. Learn. Mem.

Prostaglandins Other Lipid Mediat.

Mol. Cell. Neurosci.

Gene

Biochem. Biophys. Res. Commun.

Behav. Brain Res.

Prog. Lipid Res.

Brain Res.

Biochem. Biophys. Res. Commun.

Dev. Biol.

Cell

Neurochem. Int.

J. Biol. Chem.

Brain Res.

Dev. Biol.

Mol. Cell. Neurosci.

Neurochem. Int.

Neurochem. Int.

Biochem. Biophys. Res. Commun.

J. Psychiatr. Res.

Eur. J. Pharmacol.

Mol. Cell. Neurosci.

J. Biol. Chem.

Neuroscience

Expression of autotaxin and acylglycerol kinase in proliferative vitreoretinal epiretinal membranes

Acta Ophthalmol.

Altered lipid metabolism in brain injury and disorders

Subcell. Biochem.

A rat G protein-coupled receptor selectively expressed in myelin-forming cells

Eur. J. Neurosci.

Edg-2 in myelin-forming cells: isoforms, genomic mapping, and exclusion in Charcot-Marie-Tooth disease

Glia

Modulation of invasive properties of CD133(+) glioblastoma stem cells: a role for MT1-MMP in bioactive lysophospholipid signaling

Mol. Carcinog.

A therapeutic antibody targeting BACE1 inhibits amyloid-beta production in vivo

Sci. Transl. Med.

S1P and LPA trigger Schwann cell actin changes and migration

Eur. J. Neurosci.

EDG receptors as a therapeutic target in the nervous system

Ann. N. Y. Acad. Sci.

A novel acylglycerol kinase that produces lysophosphatidic acid modulates cross talk with EGFR in prostate cancer cells

J. Cell Biol.

Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

Proteomics

Attenuation of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking LPA1 receptors

Psychopharmacology (Berl)

A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures

J. Cereb. Blood Flow Metab.

Rho-family GTPases modulate Ca(2 +)-dependent ATP release from astrocytes

Am. J. Physiol. Cell Physiol.

Prepulse inhibition of the startle reflex: a window on the brain in schizophrenia

Curr. Top. Behav. Neurosci.

Lysophosphatidic acid induces endothelial cell death by modulating the redox environment

Am. J. Physiol.

Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: common features with mechanosensitivity

J. Physiol.