Lysophospholipid (LPL) has long been recognized as a membrane phospholipid metabolite. Recently, however, the LPL has emerged as a candidate for diagnostic and pharmacological interest. LPLs include lysophosphatidic acid (LPA), alkyl glycerol phosphate (AGP), cyclic phosphatidic acid (cPA), and sphingosine-1-phosphate (S1P). These biologically active lipid mediators serve to promote a variety of responses that include cell proliferation, migration, and survival. These LPL-related responses are mediated by cell surface G-protein-coupled receptors and also intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). In this paper, we focus mainly on the most recent findings regarding the biological function of nuclear receptor-mediated lysophospholipid signaling in mammalian systems, specifically as they relate to health and diseases. Also, we will briefly review the biology of PPARγ and then provide an update of lysophospholipids PPARγ ligands that are under investigation as a therapeutic compound and which are targets of PPARγ relevant to diseases. 1. Introduction Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor superfamily, many of which function as ligand-activated transcription factors [1]. Synthetic agonists of PPARγ include the thiazolidinedione (TZD) class of drugs, which are widely used to improve insulin sensitivity in type II diabetes. Despite the beneficial effects of PPARγ on glucose and lipid homeostasis, excess PPARγ activity can be deleterious. These classical PPARγ agonists elicit a variety of side effects, including weight gain, edema, increased fat mass, and tumor formation in rodents [2]. In contrast, there have been many reports in which the putative physiological agonists of PPARγ have been identified [3–5]. LPA is a naturally occurring phospholipid with growth-like effects in almost every mammalian cell type. LPAs elicit their biological responses through eight plasma membrane receptors [6] and intracellularly through the PPARγ [3, 4]. Although LPA derived from hydrolysis of plasma membrane phospholipids is established as a ligand for G-coupled cell surface LPA receptor, studies suggested that LPA might also enter cells to activate PPARγ. PPARγ plays a role in regulating lipid and glucose homeostasis, cell proliferation, apoptosis, and inflammation [7, 8]. These pathways have a direct impact on human diseases in obesity, diabetes, atherosclerosis, and cancer [9–11]. On the other hand, cyclic phosphatidic acid (cPA), similar in structure to LPA, can be generated
References
[1]
R. M. Evans, “The nuclear receptor superfamily: a Rosetta stone for physiology,” Molecular Endocrinology, vol. 19, no. 6, pp. 1429–1438, 2005.
[2]
H. E. Lebovitz, “Differentiating members of the thiazolidinedione class: a focus on safety,” Diabetes/Metabolism Research and Reviews, vol. 18, supplement 2, pp. S23–S29, 2002.
[3]
T. M. McIntyre, A. V. Pontsler, A. R. Silva et al., “Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 1, pp. 131–136, 2003.
[4]
T. Tsukahara, R. Tsukahara, S. Yasuda et al., “Different residues mediate recognition of 1-O-oleyl-lysophosphatidic acid and rosiglitazone in the ligand binding domain of peroxisome proliferator-activated receptor,” Journal of Biological Chemistry, vol. 281, no. 6, pp. 3398–3407, 2006.
[5]
F. J. Schopfer, Y. Lin, P. R. S. Baker et al., “Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor γ ligand,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 7, pp. 2340–2345, 2005.
[6]
W. H. Moolenaar, “Lysophosphatidic acid, a multifunctional phospholipid messenger,” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12949–12952, 1995.
[7]
M. Ricote and C. K. Glass, “PPARs and molecular mechanisms of transrepression,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 926–935, 2007.
[8]
P. Tontonoz and B. M. Spiegelman, “Fat and beyond: the diverse biology of PPARγ,” Annual Review of Biochemistry, vol. 77, pp. 289–312, 2008.
[9]
T. A. Cock, S. M. Houten, and J. Auwerx, “Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm,” EMBO Reports, vol. 5, no. 2, pp. 142–147, 2004.
[10]
C. Duval, G. Chinetti, F. Trottein, J. C. Fruchart, and B. Staels, “The role of PPARs in atherosclerosis,” Trends in Molecular Medicine, vol. 8, no. 9, pp. 422–430, 2002.
[11]
W. L. Yang and H. Frucht, “Activation of the PPAR pathway induces apoptosis and COX-2 inhibition in HT-29 human colon cancer cells,” Carcinogenesis, vol. 22, no. 9, pp. 1379–1383, 2001.
[12]
K. Murakami-Murofushi, A. Uchiyama, Y. Fujiwara et al., “Biological functions of a novel lipid mediator, cyclic phosphatidic acid,” Biochimica et Biophysica Acta, vol. 1582, no. 1–3, pp. 1–7, 2002.
[13]
K. Murakami-Murofushi, S. Kobayashi, K. Onimura et al., “Selective inhibition of DNA polymerase-α: family with chemically synthesized derivatives of PHYLPA, a unique Physarum lysophosphatidic acid,” Biochimica et Biophysica Acta, vol. 1258, no. 1, pp. 57–60, 1995.
[14]
Y. Fujiwara, “Cyclic phosphatidic acid—a unique bioactive phospholipid,” Biochimica et Biophysica Acta, vol. 1781, no. 9, pp. 519–524, 2008.
[15]
T. Tsukahara, R. Tsukahara, Y. Fujiwara et al., “Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARγ by cyclic phosphatidic acid,” Molecular Cell, vol. 39, no. 3, pp. 421–432, 2010.
[16]
T. Tsukahara, S. Hanazawa, T. Kobayashi, Y. Iwamoto, and K. Murakami-Murofushi, “Cyclic phosphatidic acid decreases proliferation and survival of colon cancer cells by inhibiting peroxisome proliferator-activated receptor γ,” Prostaglandins and Other Lipid Mediators, vol. 93, no. 3-4, pp. 126–133, 2010.
[17]
M. ] Mukai, F. Imamura, M. Ayaki et al., “Inhibition of tumor invasion and metastasis by a novel lysophosphatidic acid (cyclic LPA),” International Journal of Cancer, vol. 81, pp. 918–922, 1999.
[18]
M. Mukai, T. Iwasaki, M. Tatsuta et al., “Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion,” International Journal of Oncology, vol. 22, no. 6, pp. 1247–1256, 2003.
[19]
J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002.
[20]
B. Kie？-Wilk, A. Dembińska-Kie？, A. Olszanecka, M. Bodzioch, and K. Kawecka-Jaszcz, “The selected pathophysiological aspects of PPARs activation,” Journal of Physiology and Pharmacology, vol. 56, no. 2, pp. 149–162, 2005.
[21]
P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994.
[22]
G. Medina-Gomez, S. Virtue, C. Lelliott et al., “The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-γ2 isoform,” Diabetes, vol. 54, no. 6, pp. 1706–1716, 2005.
[23]
D. S. Lala, R. Mukherjee, I. G. Schulman et al., “Activation of specific RXR heterodimers by an antagonist of RXR homodimers,” Nature, vol. 383, no. 6599, pp. 450–453, 1996.
[24]
R. N. Cohen, “Nuclear receptor corepressors and PPARgamma,” Nucl Recept Signal, vol. 4, article e003, 2006.
[25]
P. Puigserver and B. M. Spiegelman, “Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator,” Endocrine Reviews, vol. 24, no. 1, pp. 78–90, 2003.
[26]
T. S. Mikkelsen, M. Ku, D. B. Jaffe et al., “Genome-wide maps of chromatin state in pluripotent and lineage-committed cells,” Nature, vol. 448, no. 7153, pp. 553–560, 2007.
[27]
B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ,” Cell, vol. 83, no. 5, pp. 803–812, 1995.
[28]
G. Tigyi, “Aiming drug discovery at lysophosphatidic acid targets,” British Journal of Pharmacology, vol. 161, no. 2, pp. 241–270, 2010.
[29]
G. Tigyi and R. Miledi, “Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochromocytoma cells,” Journal of Biological Chemistry, vol. 267, no. 30, pp. 21360–21367, 1992.
[30]
G. Tigyi and A. L. Parrill, “Molecular mechanisms of lysophosphatidic acid action,” Progress in Lipid Research, vol. 42, no. 6, pp. 498–526, 2003.
[31]
A. Schober and W. Siess, “Lysophosphatidic acid in atherosclerotic diseases,” British Journal of Pharmacology, vol. 167, pp. 465–482, 2012.
[32]
G. A. Fishbein and M. C. Fishbein, “Arteriosclerosis: rethinking the current classification,” Archives of Pathology and Laboratory Medicine, vol. 133, no. 8, pp. 1309–1316, 2009.
[33]
N. Shibata and C. K. Glass, “Regulation of macrophage function in inflammation and atherosclerosis,” Journal of Lipid Research, vol. 50, supplement, pp. S277–S281, 2009.
[34]
R. G. Gerrity, “The role of the monocyte in atherogenesis. I. Transition of blood-borne monocytes into foam cells in fatty lesions,” American Journal of Pathology, vol. 103, no. 2, pp. 181–190, 1981.
[35]
K. Yoshida, W. Nishida, K. Hayashi et al., “Vascular remodeling induced by naturally occurring unsaturated lysophosphatidic acid in vivo,” Circulation, vol. 108, no. 14, pp. 1746–1752, 2003.
[36]
C. Zhang, D. L. Baker, S. Yasuda et al., “Lysophosphatidic acid induces neointima formation through PPARγ activation,” Journal of Experimental Medicine, vol. 199, no. 6, pp. 763–774, 2004.
[37]
C. H. Lee and R. M. Evans, “Peroxisome proliferator-activated receptor-γ in macrophage lipid homeostasis,” Trends in Endocrinology and Metabolism, vol. 13, no. 8, pp. 331–335, 2002.
[38]
M. Febbraio, D. P. Hajjar, and R. L. Silverstein, “CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism,” Journal of Clinical Investigation, vol. 108, no. 6, pp. 785–791, 2001.
[39]
P. C. Moore, M. A. Ugas, D. K. Hagman, S. D. Parazzoli, and V. Poitout, “Evidence against the involvement of oxidative stress in fatty acid inhibition of insulin secretion,” Diabetes, vol. 53, no. 10, pp. 2610–2616, 2004.
[40]
N. Ohgami, R. Nagai, M. Ikemoto et al., “CD36, a member of the class B scavenger receptor family, as a receptor for advanced glycation end products,” Journal of Biological Chemistry, vol. 276, no. 5, pp. 3195–3202, 2001.
[41]
M. S. Brown, S. K. Basu, and J. R. Falck, “The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages,” Journal of Supramolecular and Cellular Biochemistry, vol. 13, no. 1, pp. 67–81, 1980.
[42]
D. J. Gallagher and N. Kemeny, “Metastatic colorectal cancer: from improved survival to potential cure,” Oncology, vol. 78, no. 3-4, pp. 237–248, 2010.
[43]
A. Manzano and P. Perez-Segura, “Colorectal cancer chemoprevention: is this the future of colorectal cancer prevention?” Scientific World Journal, vol. 2012, Article ID 327341, 8 pages, 2012.
[44]
E. Saez, P. Tontonoz, M. C. Nelson et al., “Activators of the nuclear receptor PPARγ enhance colon polyp formation,” Nature Medicine, vol. 4, no. 9, pp. 1058–1061, 1998.
[45]
H. P. Koeffler, “Peroxisome proliferator-activated receptor γ and cancers,” Clinical Cancer Research, vol. 9, no. 1, pp. 1–9, 2003.
[46]
G. D. Girnun, W. M. Smith, S. Drori et al., “APC-dependent suppression of colon carcinogenesis by PPARγ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13771–13776, 2002.
[47]
P. Sarraf, E. Mueller, W. M. Smith et al., “Loss-of-function mutations in PPARγ associated with human colon cancer,” Molecular Cell, vol. 3, no. 6, pp. 799–804, 1999.
[48]
H. Sato, S. Ishihara, K. Kawashima et al., “Expression of peroxisome proliferator-activated receptor (PPAR)γ in gastric cancer and inhibitory effects of PPARγ agonists,” British Journal of Cancer, vol. 83, no. 10, pp. 1394–1400, 2000.
[49]
D. Shen, C. Deng, and M. Zhang, “Peroxisome proliferator-activated receptor γ agonists inhibit the proliferation and invasion of human colon cancer cells,” Postgraduate Medical Journal, vol. 83, no. 980, pp. 414–419, 2007.
[50]
T. Tsukahara and H. Haniu, “Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells,” Biochemical and Biophysical Research Communications, vol. 424, pp. 524–529, 2012.
[51]
G. Lee, F. Elwood, J. McNally et al., “T0070907, a selective ligand for peroxisome proliferator-activated receptor γ, functions as an antagonist of biochemical and cellular activities,” Journal of Biological Chemistry, vol. 277, no. 22, pp. 19649–19657, 2002.
[52]
T. Tsukahara, “The role of PPARgamma in the transcriptional control by agonists and antagonists,” PPAR Research, vol. 2012, Article ID 362361, 2012.
[53]
T. Tsukahara and K. Murakami-Murofushi, “Release of cyclic phosphatidic acid from gelatin-based hydrogels inhibit colon cancer cell growth and migration,” Scientific Reports, vol. 2, p. 687, 2012.
[54]
M. Krotkiewski, P. Bjorntorp, L. Sjostrom, and U. Smith, “Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution,” Journal of Clinical Investigation, vol. 72, no. 3, pp. 1150–1162, 1983.
[55]
P. Bjorntorp, “Abdominal obesity and the metabolic syndrome,” Annals of Medicine, vol. 24, no. 6, pp. 465–468, 1992.
[56]
H. Green and M. Meuth, “An established pre adipose cell line and its differentiation in culture,” Cell, vol. 3, no. 2, pp. 127–133, 1974.
[57]
T. Tsukahara, S. Hanazawa, and K. Murakami-Murofushi, “Cyclic phosphatidic acid influences the expression and regulation of cyclic nucleotide phosphodiesterase 3B and lipolysis in 3T3-L1 cells,” Biochemical and Biophysical Research Communications, vol. 404, no. 1, pp. 109–114, 2011.
[58]
J. Ostman, P. Arner, P. Engfeldt, and L. Kager, “Regional differences in the control of lipolysis in human adipose tissue,” Metabolism: Clinical and Experimental, vol. 28, no. 12, pp. 1198–1205, 1979.
[59]
G. Y. Carmen and S. M. Víctor, “Signalling mechanisms regulating lipolysis,” Cellular Signalling, vol. 18, no. 4, pp. 401–408, 2006.
[60]
Y. H. Jeon, Y. S. Heo, C. M. Kim et al., “Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development,” Cellular and Molecular Life Sciences, vol. 62, no. 11, pp. 1198–1220, 2005.
[61]
E. Degerman, F. Ahmad, Y. W. Chung et al., “From PDE3B to the regulation of energy homeostasis,” Current Opinion in Pharmacology, vol. 11, pp. 676–682, 2011.
