Lysophosphatidic acid (1-acyl-2-lyso-snglycero-3-phosphate, LPA) is a multifunctional lipid mediator found in a variety of organisms that span the phylogenetic tree from humans to plants. Although its physiological function is not clearly understood, LPA is a potent regulator of mammalian cell proliferation; it is one of the major mitogens found in blood serum. Lysophosphatidic acid (LPA) is an intercellular lipid mediator with growth factor-like activities. LPA is rapidly produced and released from activated platelets to influence target cells by activating a specific G protein-coupled receptor (GPCR) that is present in numerous cell types. Albumin-bound LPA is an abundant constituent of serum and can account for much of the biologic activity of serum. Moolenaar et al. (1997) reviewed progress in the understanding of LPA action and signaling
NCBI Summary:
The integral membrane protein encoded by this gene is a lysophosphatidic acid (LPA) receptor from a group known as EDG receptors. These receptors are members of the G protein-coupled receptor superfamily. Utilized by LPA for cell signaling, EDG receptors mediate diverse biologic functions, including proliferation, platelet aggregation, smooth muscle contraction, inhibition of neuroblastoma cell differentiation, chemotaxis, and tumor cell invasion. Many transcript variants encoding a few different isoforms have been identified for this gene. [provided by RefSeq, Oct 2020]
Lysophosphatidic acid improves oocyte quality during IVM by activating the ERK1/2 pathway in cumulus cells and oocytes. Ma Y et al. (2021) Oocyte IVM technology is an option for fertility preservation in some groups of patients, such as those with polycystic ovary syndrome, patients with ovarian hyperstimulation syndrome, and for patients with cancer. However, the developmental potential of oocytes from IVM still needs to improve. Several previous studies have reported that lysophosphatidic acid (LPA) promotes glucose metabolism, cumulus cell (CC) expansion, and oocyte nuclear maturation. However, the effect of LPA on oocyte cytoplasmic maturation, particularly mitochondrial function, has rarely been studied and the underlying mechanism is largely unknown, which impedes (pre)clinical applications of LPA. In this study, cumulus-oocyte complexes (COCs) and cumulus-denuded germinal vesicle oocytes (DOs) were treated with various concentrations of LPA during IVM, in the presence or absence of the oxidative stressor cyclophosphamide (CTX). In both normal and CTX-damaged COCs, the 25 μM LPA group exhibited improved CC expansion capacity, a higher nuclear maturation rate, and superior mitochondrial function, compared to no LPA treatment. When the concentration of LPA was over 40 μM, detrimental effects of LPA on oocyte maturation occurred. Compared with COCs, the addition of LPA slightly improved oocyte nuclear and cytoplasmic maturation of DOs, but this was not statistically significant. We observed that LPA promotes the activation of ERK1/2, although this was not statistically significant in DOs. Furthermore, LPA could not reverse the negative effect of CC expansion and mitochondrial function after inactivation of ERK1/2 by U0126. RNA-Sequencing and RT-PCR results showed that LPA upregulated several ERK1/2 downstream genes related to CC expansion, such as Areg, Cited4, and Ptgs2. This study demonstrates that LPA improves oocyte quality during IVM through the activation of ERK1/2 pathway CCs and oocytes, which provides evidence for the potential addition of LPA to IVM medium.//////////////////The effect of lysophosphatidic acid during in vitro maturation of bovine cumulus-oocyte complexes: cumulus expansion, glucose metabolism and expression of genes involved in the ovulatory cascade, oocyte and blastocyst competence. Boruszewska D et al. (2015) In the cow, lysophosphatidic acid (LPA) acts as an auto-/paracrine factor, through its receptors LPAR1-4, on oocytes and cumulus cells during in vitro maturation (IVM). The aim of the present work was to determine the effect of LPA during IVM of bovine oocytes on: 1) oocyte maturation; 2) apoptosis of COCs; 3) expression of genes involved in developmental competence and apoptosis in bovine oocytes and subsequent blastocysts; 4) cumulus expansion and expression of genes involved in the ovulatory cascade in cumulus cells; 5) glucose metabolism and expression of genes involved in glucose utilization in cumulus cells; 6) cleavage and blastocyst rates on Day 2 and Day 7 of in vitro culture, respectively. Cumulus-oocyte complexes (COCs) were matured in vitro in the presence or absence of LPA (10(-5)M) for 24h. Following maturation, we determined: oocyte maturation stage, cumulus expansion, COCs apoptosis and glucose and lactate levels in the maturation medium. Moreover, COCs were either used for gene expression analysis or fertilized in vitro. The embryos were cultured until Day 7 to assess cleavage and blastocyst rates. Oocytes, cumulus cells and blastocysts were used for gene expression analysis. Supplementation of the maturation medium with LPA enhanced oocyte maturation rates and stimulated the expression of developmental competence-related factors (OCT4, SOX2, IGF2R) in oocytes and subsequent blastocysts. Moreover, LPA reduced the occurrence of apoptosis in COCs and promoted an antiapoptotic balance in the transcription of genes involved in apoptosis (BAX and BCL2) either in oocytes or blastocysts. LPA increased glucose uptake by COCs via augmentation of GLUT1 expression in cumulus cells as well as stimulating lactate production via the enhancement of PFKP expression in cumulus cells. LPA did not affect cumulus expansion as visually assessed, however, it stimulated upstream genes of cumulus expansion cascade, AREG and EREG. Supplementation of the maturation medium with LPA improves oocyte maturation rates, decreases extent of apoptosis in COCs and sustains the expression of developmental competence related factors during oocyte maturation and subsequently affects gene expression profile at the blastocyst stage. We also demonstrate that LPA directs glucose metabolism toward the glycolytic pathway during IVM.//////////////////
Lysophosphatidic acid modulates prostaglandin signalling in bovine steroidogenic luteal cells. Kowalczyk-Zieba I et al. (2015) We examined whether lysophosphatidic acid affects prostaglandin biosynthesis, transport, and signalling in bovine steroidogenic luteal cells. The aim of the present study was to determine the influence of LPA on PGE2 and PGF2α synthesis and on the expression of enzymes involved in PG biosynthesis (PTGS2, mPGES-1, cPGES, mPGES-2, PGFS, 9-KPR), prostaglandin transporter (PGT), and prostaglandin receptors (EP1, EP2, EP3, EP4 and FP) in bovine steroidogenic luteal cells. We found that LPA inhibited PGF2α synthesis in steroidogenic luteal cells. Moreover, LPA increased mPGES1 and cPGES and decreased PGFS expression in cultured bovine steroidogenic luteal cells. Additionally, LPA stimulated EP2 and EP4 receptor and PGT expression. This study suggests that LPA activity in the bovine CL directs the physiological intraluteal balance between the two main prostanoids towards luteotropic PGE2. LPA increases mPGES1 and cPGES expression and decreases PGFS expression in bSLCs LPA stimulates EP2 and EP4 receptor and PGT expression in bSLCs LPA influences intraluteal PG balance in bSLCs LPA may support CL function and lifespan in cows The results revealed identify linkage between LPA and PG biosynthesis in the bovine CL.//////////////////Influence of lysophosphatidic acid on estradiol production and follicle stimulating hormone action in bovine granulosa cells. Boruszewska D 2013 et al.
The objective of the study was to examine the effect of lysophosphatidic acid (LPA) on 17?estradiol (E2) synthesis and follicle stimulating hormone (FSH) action in bovine granulosa cells. We found that granulosa cells in the bovine antral follicle, in addition to the uterus and the CL, are also the site of LPA synthesis and the target for LPA action in the bovine reproductive tract. Our findings suggest that LPA stimulates E2 synthesis, probably via increased expression of FSHR and 17?HSD genes.
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Influence of Lysophosphatidic Acid on Nitric Oxide Induced Luteolysis in Steroidogenic Luteal Cells in Cows. Kowalczyk-Zieba I 2013 et al.
Lysophosphatidic acid (LPA) together with its active G protein-coupled receptors are present in the corpus luteum (CL) of the cow. Under in vivo conditions, LPA stimulated P4 and PGE2 secretion during the luteal phase of the estrous cycle in heifers. Furthermore, LPA maintained P4 synthesis and actions in the bovine CL in vitro. However, the effect of this phospholipid on NO-induced functional and structural luteolysis has not been investigated. The aim of the present work was to determine the effects of LPA on: (1) NO-induced functional luteolysis, (2) NO-dependent PG synthesis and (3) NO-induced structural luteolysis, in cultured steroidogenic luteal cells. We documented that LPA reversed the inhibitory effect of NONOate, an NO donor, on P4 synthesis and PGE2/PGF2alpha ratio in cultured steroidogenic luteal cells. Additionally, LPA inhibited NO-induced apoptosis in cultured steroidogenic luteal cells via abrogation of the NO-dependent stimulatory influence on pro-apoptotic TNFalpha/TNFR1 and Fas/FasL expression, Caspase 3 activity and the Bax/Bcl2 ratio during luteal regression in the bovine CL. In conclusion, this study proves that in the presence of LPA, NO cannot induce luteolytic capacity acquisition leading to functional and structural luteolysis of bovine luteal cells.
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Budnik and Mukhopadhyay (1997) presented evidence that [3H] lysophosphatidic acid (LPA) binds to a 38-40 kDa protein in a membrane fraction prepared from luteal cells and that this phospholipid is able to induce tyrosine phosphorylation of several proteins. Furthermore, LPA upregulates forskolin- and LH/GTP-stimulated adenylyl cyclase activity by changing its Vmax.
Expression regulated by
Comment
Ovarian localization
Oocyte, Theca, Luteal cells, ovarian tumor
Comment
Bovine ovarian follicular growth and development correlate with lysophosphatidic acid expression. Sinderewicz E et al. (2017) The basis of successful reproduction is proper ovarian follicular growth and development. In addition to prostaglandins and vascular endothelial growth factor, a number of novel factors are suggested as important regulators of follicular growth and development: PGES, TFG, CD36, RABGAP1, DBI and BTC. This study focuses on examining the expression of these factors in granulosa and thecal cells that originate from different ovarian follicle types and their link with the expression of lysophosphatidic acid (LPA), known local regulator of reproductive functions in the cow. Ovarian follicles were divided into healthy, transitional, and atretic categories. The mRNA expression levels for PGES, TFG, CD36, RABGAP1, DBI and BTC in granulosa and thecal cells in different follicle types were measured by real-time PCR. The correlations among expression of enzymes synthesizing LPA (autotaxin, phospholipase A2), receptors for LPA and examined factors were measured. Immunolocalization of PGES, TFG, CD36, RABGAP1, DBI and BTC was examined by immunohistochemistry. We investigated follicle-type dependent mRNA expression of factors potentially involved in ovarian follicular growth and development, both in granulosa and thecal cells of bovine ovarian follicles. Strong correlations among receptors for LPA, enzymes synthesizing LPA, and the examined factors in healthy and transitional follicles were observed, with its strongest interconnection with TFG, DBI and RABGAP1 in granulosa cells, and TFG in thecal cells; whereas no correlations in atretic follicles were detected. A greater number of correlations were found in thecal cells than in granulosa cells as well as in healthy follicles than in transitional follicles. These data indicate the role of LPA in the growth, development and physiology of the bovine ovarian follicle.//////////////////
Liliom et al. (1996) reported that Xenopus oocytes express multiple receptors for LPA-like lipid mediators. In Xenopus laevis oocytes, both lysophosphatidic acid (LPA) and a cyclic phosphate-containing analogue 1-acyl-sn-glycero-2,3-cyclic phosphate (cLPA) isolated from Physarum polycephalum activated oscillatory Cl-currents. cLPA elicited oscillatory currents only when applied extracellularly and, similarly to LPA, evoked homologous desensitization. cLPA applied to oocytes previously desensitized by LPA failed to elicit a current, indicating that LPA completely desensitized cLPA receptors. In contrast, when oocytes were desensitized by cLPA, LPA still evoked large currents. The lack of heterologous desensitization between cLPA and LPA indicates that the former acts on a distinct receptor subpopulation(s), which is also activated by LPA. Guo et al. (1996) reported the molecular cloning of a high-affinity receptor for the growth factor-like lipid mediator lysophosphatidic acid from Xenopus oocytes. The predicted structure of this protein of 372 amino acids contains features common to members of the seven transmembrane receptor superfamily with a predicted extracellular amino and intracellular carboxyl terminus.
Fang X, et al 2000 reported the role of lysophospholipid growth factors in the initiation, progression,
metastases, and management of ovarian cancer.
Levels of lysophosphatidic acid (LPA) and lysophosphatidylcholine (LPC) are
elevated in the plasma and ascites of ovarian cancer patients, but not in most other
tumor types. LPA increases cell proliferation, cell survival, resistance to
cisplatin, cell shrinkage, and production of vascular endothelial growth factor,
urokinase plasminogen activator, and LPA itself in ovarian cancer cells, but not in normal ovarian surface epithelial cells. PSP24 and members of the endothelial
differentiation gene (EDG) family (EDG1, EDG2, EDG4, and EDG7) of G protein-coupled receptors mediate LPA signaling. Ovarian cancer cell lines do
not express EDG1 mRNA, have variable EDG2 mRNA and protein levels, and frequently exhibit levels of EDG4 mRNA and protein, suggesting that EDG4 may contribute to the deleterious effects of LPA in ovarian cancer. In contrast,
activation of the EDG2 LPA receptor on ovarian cancer cells may lead to
apoptosis and counter the effects of other LPA receptors.
Budnik LT, et al 2003 investigated the mechanism of lysophosphatidic acid (LPA) signaling in ovarian theca cells and observed that stimulation with this bioactive lipid markedly enhanced Thr/Tyr phosphorylation of the MAPK ERK1/2. Activation of ERK was transient, showing a peak at 5 min that declined thereafter, and was not associated with a concomitant nuclear translocation of the enzyme, suggesting that a cytosolic tyrosine phosphatase may be responsible for switching off the signal. Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (peaking at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A. This functional inhibition of either Gi or Ras failed, however, to affect the LPA-induced ERK-phosphorylation. Surprisingly, functional inhibition of Rho-GTPase, in C3-exotoxin-lipofected cells, markedly reduced LPA-stimulated phosphorylation of ERK, without affecting the EGF-induced stimulation of MAPK. Theca cells labeled with anti-LPA1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LPA1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LPA1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.
Follicle stages
Primordial, Antral, Corpus luteum
Comment
Differential effects of lysolipids on steroid synthesis in cells expressing endogenous LPA2 receptor Budnik LT, et al 2005 .
Incubation of ovarian luteal cells with bioactive lipid mediator, lysophosphatidic acid (LPA) for 180 min. abolishes gonadotropin-induced steroid production with no attenuation of the cyclic AMP accumulation. Treatment with the lysolipid also diminishes [14C] steroid production in cells preloaded with either [14C] cholesterol or [14C] acetate. Neither the expression of StAR (steroidogenic acute regulatory-protein) protein nor the in vitro steroid synthesis is affected in isolated mitochondrial fractions. The LPA-induced attenuation of the steroid production occurs only during the mid cycle corpus luteum and is associated with a transient endogenous expression of mRNA for the LPA2 receptor (with no concomitant changes in the expression of LPA1 receptor). Expression of LPA2 is accompanied by LPA-induced sphingosine-1-phosphate (S1P) production. Since in the presence of sphingosine kinase inhibitor, dihydrosphingosine, luteal cells can overcome the inhibitory effects of LPA on steroid synthesis, we suggest the possible requirement of intracellular S1P production. Interestingly, no LPA-induced inhibition of 8Br-cAMP stimulated progesterone synthesis can be detected in Leydig tumor cell line, MA10 cells, which is expressing LPA2 receptor only, but no LPA1. Surprisingly however, exogenous S1P is inhibiting agonist stimulated progesterone in both cell types, by inhibiting cyclic AMP accumulation suggesting different mechanisms of action.