Central Journal of Endocrinology, Diabetes & Obesity

Editorial Corresponding author Tamotsu Tsukahara, Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Cyclic : An Daigaku, Uchinada, Ishikawa 920-0293, Japan, E-mail: [email protected] Submitted: 25 August 2013 Endogenous Antagonist of Accepted: 26 August 2013 Published: 29 August 2013 PPARγ Copyright © 2013 Tsukahara et al. Tamotsu Tsukahara1*, Yoshikazu Matsuda2, Hisao Haniu3 and Kimiko Murakami- Murofushi4 OPEN ACCESS 1Department of Hematology and Immunology, Kanazawa Medical University, Japan 2Clinical Pharmacology Educational Center, Nihon Pharmaceutical University, Japan 3Department of Orthopaedic Surgery, Shinshu University School of Medicine, Japan 4Endowed Research Division of Human Welfare Sciences, Ochanomizu University, Japan

Lysophospholipids (LPLs) have long been recognized as (PC) to generate and bioactive membrane phospholipid metabolites. LPLs are small bioactive lipid, has been implicated in signal transduction, membrane lipid molecules that are characterized by a single carbon 10]. There are two chain and a polar head group. LPLs have been implicated in a PLD isoenzymes, PLD1 and PLD2, which are expressed in a number of pathological states and human diseases. LPLs include varietytrafficking, of tissues and cytoskeletal and cells [ 11reorganization]. We labeled [ cultured cells with lysophosphatidic acid (LPA), alkyl-glycerol phosphate (AGP), [32P]-orthophosphate for 30 min and compared that to [32P]- sphingoshine-1-phosphate, and cyclic phosphatidic acid (cPA). labeled cPA from vehicle control cells using two-dimensional thin In recent years, cPA has been reported to be a target for many layer chromatography. Furthermore, we used CHO cells stably diseases, including obesity [1], atherosclerosis [2], cancer [3], expressing PLD1 or PLD2 or catalytically inactive forms of PLD1 and pain [4]. cPA is an analog of LPA that has a 5-atom ring and PLD2 to delineate the roles of the PLDs in cPA formation. linking the phosphate to 2 of the glycerol carbon atoms. cPA is PLD2-expressing cell lines had an elevated basal level of cPA found in diverse organisms, from slime molds to humans [5]. The and higher PMA-stimulated cPA production relative to control concentration of cPA in human serum is estimated to be around wild-type (WT) cells [2 role of PLD2 activation in stimulus-coupled cPA production. In formation, adipocytic differentiation, lipid accumulation, and recent years, the physiological]. This findingand pathophysiological provides evidence functions for the 100 nM. cPA, along with PPARγ agonists, prevents neointima macrophages [2 upregulation of PPARγ-target transcription in mouse of peroxisome proliferator-activated receptor γ (PPARγ)2]. ligands cPA offers new therapeutic]. These findings opportunities support our to improvehypothesis the that quality cPA have been explored. In our recent work, we identified cPA as an Role of cPA in lipid signaling-related diseases ofis anpatient endogenous care. Here, antagonist we discuss of PPARγ. the current These knowledge data suggest on that the endogenous PPARγ antagonist generated by PLD2 [ pathophysiological actions of cPA and attempt to link them with Recent reports have been shown that LPA plays an important particular targets. role in the vascular system [12]. LPA is produced in serum after the activation of biochemical pathways linked to platelet Enzymatic formation of cPA 13] and rosiglitazone Murakami-Murofushi et al. [6] reported that cPA is detected (ROSI) induce neointima when applied topically within the carotidactivation. artery The PPARγ [14]. Neointimal agonists alkyl-LPA lesions [ are characterized by Many of the activities of cPA have been attributed to albumin- the accumulation of cells within the arterial wall and are a in mammalian biological fluids, including human serum. prelude to atherosclerotic disease [14]. In recent reports, the cPA by (ATX) under non-physiological conditions knockdown of 1-acyl-sn-glycerol-3-phosphate acyltransferase appearedassociated in lipid 2006 factors. [7,8]. ATX, The also first known report as ofphosphodiesterase the generation of2, 15]. AGPAT2 is a secreted important for generating the lipid signaling is located the endoplasmic reticulum membrane and converts molecule LPA [9]. ATX has lysophospholipase D activity and βLPA (AGPAT2) to phosphatidic resulted acid in increased(PA). Mutations levels in of this cPA gene [ have been converts lysophosphatidylcholine (LPC) into LPA. The enzymatic associated with congenital generalized lipodystrophy (CGL) [16]. formation and function of cPA are poorly characterized. In Lipodystrophies, including CGL, are heterogeneous acquired or addition, the identity of the enzyme that contributes to the inherited disorders characterized by the selective loss of adipose tissue and development of severe insulin resistance. AGPAT2 is a member of a family of proteins with acyltransferase activity, anformation enzyme of that cPA can in generate biological cPA fluids [2]. PLD, remains which unknown. hydrolyzes In and mediates the acylation of LPA into PA [17]. Subauste et al. our recent work, we identified D2 (PLD2) as

Cite this article: Tsukahara T, Matsuda Y, Haniu H, Murakami-Murofushi K (2013) Cyclic Phosphatidic Acid: An Endogenous Antagonist of PPARg. J Endo- crinol Diabetes Obes 1(1): 1005. Tsukahara et al. (2013) Email: [email protected] Central recently reported that overexpression of AGPAT2 decreases 5. Murakami-Murofushi K, Kobayashi S, Onimura K, Matsumoto M, cPA levels [18]. Furthermore, the knockdown of AGPAT2 results Shioda M, Yoshida S, et al. Selective inhibition of DNA polymerase- in increases in the level of the saturated form of cPA 18:0 and alpha family with chemically synthesized derivatives of PHYLPA, a cPA16:0 [15 1258: 57-60. unique Physarum lysophosphatidic acid. Biochim Biophys Acta. 1995; dependent luciferase]. They also activation. assessed These the effect data ofsuggest AGPAT2 that on AGPAT2 PPARγ 6. Murakami-Murofushi K, Uchiyama A, Fujiwara Y, Kobayashi T, transactivation and found that AGPAT2 increases PPARγ-

1-7.Kobayashi S, Mukai M, et al. Biological functions of a novel lipid modulates PPARγ activity and glycerolipid levels. However, the mediator, cyclic phosphatidic acid. Biochim Biophys Acta. 2002; 1582: physiological context of these mechanisms in PPARγ signaling is still unclear. Further clarification of the PPARγ-cPA axis will et al. Carba analogs of cyclic phosphatidic acid are selective inhibitors In conclusion, we hope that we have provided interesting insights 7. Baker DL, Fujiwara Y, Pigg KR, Tsukahara R, Kobayashi S, Murofushi H, allow the synthesis of novel drugs that modulate PPARγ function. 2006; 281: 22786-93. cPA axis in various cardiovascular diseases. We expect that the of autotaxin and cancer cell invasion and metastasis. J Biol Chem. reviewsinto these presented recent advances in this in issue, elucidating which focusthe roles on of the the interplay PPARγ- 8. Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, Aoki J, et

Chem. 2006; 281: 26081-8. useful for those interested in phospholipid biology, nuclear al. Cyclic phosphatidic acid is produced by autotaxin in blood. J Biol receptorbetween PPARγ function, and and the their cardiovascular intersection system, with cardiovascular will be highly pathologies. Pharmacol. 2010; 161: 241-270. 9. Tigyi G. Aiming drug discovery at lysophosphatidic acid targets. Br J ACKNOWLEDGMENTS 10. 11. ExtonCockcr JH.oft RegulationS. Signalling of roles phospholipase of mammalian D. FEBS phospholipase Lett. 2002; 531:D1 and 58-61. D2. This work was supported by research grants from the Astellas Cell Mol Life Sci. 2001; 58: 1674-1687. Foundation for Research on Metabolic Disorders (to Tamotsu 12. Schober A and Siess W. Lysophosphatidic acid in atherosclerotic Tsukahara), Takeda Science Foundation (to Tamotsu Tsukahara),

Tsukahara) from the Japan Society for the Promotion of Science 13. Tsukaharadiseases. Br JT, Pharmacol. Tsukahara 2012; R, 167: Yasuda 465-482. S, Makarova N, Valentine (JSPS),Grants-in-Aid and the for Princess Scientific Takamatsu Research (B) Cancer 25293274 Research (to FundTamotsu (to WJ, Allison P, et al. Different residues mediate recognition of 1-O-oleyllysophosphatidic acid and rosiglitazone in the ligand binding Kimiko Murakami-Murofushi). Chem. 2006; 281: 3398-3407. REFERENCES domain of peroxisome proliferator-activated receptor gamma. J Biol 1. Tsukahara T, Hanazawa S, Murakami-Murofushi K. Cyclic phosphatidic al. Lysophosphatidic acid induces neointima formation through 14. ZhangPPARgamma C, Baker activation. DL, Yasuda J Exp S, Med. Makarova 2004; 199: N, Balazs 763-774. L, Johnson LR, et Resacid Commun. influences 2011; the 404: expression 109-14. and regulation of cyclic nucleotide 3B and lipolysis in 3T3-L1 cells. Biochem Biophys Alterations in lipid signaling underlie lipodystrophy secondary to 2. Tsukahara T, Tsukahara R, Fujiwara Y, Yue J, Cheng Y, Guo H, et al. 15. SubauAGPAT2ste mutations. AR, Das AK, Diabetes. Li X, Elliot2012; B,61: Evans 2922-2931. C, El Azzouny M, et al. Phospholipase D2-dependent inhibition of the nuclear hormone receptor PPARgamma by cyclic phosphatidic acid. Mol Cell. 2010; 39: 421-32. AM, et al. AGPAT2 is mutated in congenital generalized lipodystrophy 16. Agarwallinked to AK, Arioglu E, 9q34. De Almeida Nat Genet. S, Akkoc2002; 31: N, Taylor21-23. SI, Bowcock 3. Tsukahara T, Hanazawa S, Kobayashi T, Iwamoto Y, Murakami- Murofushi K. Cyclic phosphatidic acid decreases proliferation and 17. Eberhardt C, Gray PW, Tjoelker LW. Human lysophosphatidic acid survival of colon cancer cells by inhibiting peroxisome proliferator- acyltransferase. cDNA cloning, expression, and localization to

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Cite this article Tsukahara T, Matsuda Y, Haniu H, Murakami-Murofushi K (2013) Cyclic Phosphatidic Acid: An Endogenous Antagonist of PPARg. J Endocrinol Diabetes Obes 1(1): 1005.

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