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• W2073631244 abstract "A recent study in Molecular Cell (Tsukahara et al., 2010Tsukahara T. Tsukahara R. Fujiwara Y. Yue J. Cheng Y. Guo H. Bolen A. Zhang C. Balazs L. Re F. et al.Mol. Cell. 2010; 39: 421-432Abstract Full Text Full Text PDF Scopus (93) Google Scholar) identifies cyclic phosphatidic acid (CPA) as a naturally occurring PPARγ antagonist that can be generated from lysophospholipids by signal-dependent activation of phospholipase D2. This endogenous CPA regulates PPARγ functions required for adipogenesis, glucose homeostasis, and vascular wall biology. A recent study in Molecular Cell (Tsukahara et al., 2010Tsukahara T. Tsukahara R. Fujiwara Y. Yue J. Cheng Y. Guo H. Bolen A. Zhang C. Balazs L. Re F. et al.Mol. Cell. 2010; 39: 421-432Abstract Full Text Full Text PDF Scopus (93) Google Scholar) identifies cyclic phosphatidic acid (CPA) as a naturally occurring PPARγ antagonist that can be generated from lysophospholipids by signal-dependent activation of phospholipase D2. This endogenous CPA regulates PPARγ functions required for adipogenesis, glucose homeostasis, and vascular wall biology. The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family of ligand-dependent transcription factors that plays essential roles in adipogenesis and glucose homeostasis and the molecular target of the thiazolidinedione (TZD) class of insulin-sensitizing agents used clinically to treat type 2 diabetes (Spiegelman, 1998Spiegelman B.M. Diabetes. 1998; 47: 507-514Crossref PubMed Scopus (1588) Google Scholar). PPARγ has a large, promiscuous ligand-binding pocket and can be activated by a diverse spectrum of phospholipid and fatty acid metabolites, including select leukotrienes, prostaglandins, modified fatty acids, and oxidized phospholipids (Chou et al., 2007Chou W.L. Chuang L.M. Chou C.C. Wang A.H. Lawson J.A. FitzGerald G.A. Chang Z.F. J. Biol. Chem. 2007; 282: 18162-18172Crossref PubMed Scopus (67) Google Scholar, and references therein). Despite the abundance of naturally occurring molecules that activate PPARγ in cell-based assays, the identities of the endogenous ligands of PPARγ that are of actual physiological importance in specific tissue contexts remain poorly defined. A recent paper published by Tsukahara and colleagues in Molecular Cell (Tsukahara et al., 2010Tsukahara T. Tsukahara R. Fujiwara Y. Yue J. Cheng Y. Guo H. Bolen A. Zhang C. Balazs L. Re F. et al.Mol. Cell. 2010; 39: 421-432Abstract Full Text Full Text PDF Scopus (93) Google Scholar) provides the first evidence for an endogenously produced PPARγ antagonist. They report that cyclic phosphatidic acid (CPA), a simple lysophospholipid of poorly characterized function, binds to PPARγ with nanomolar affinity and antagonizes its activation by synthetic or naturally occurring agonists. Under physiological conditions, PPARγ positively regulates gene expression by binding as a heterodimer with RXRs to PPAR response elements in the vicinity of target genes. Agonists increase PPARγ-dependent gene expression by stimulating interactions with coactivators, such as PGC1α, SRC proteins, and the TRAP220 component of the mediator complex, and simultaneously reducing interactions with corepressors, such as NCoR and SMRT (Figure 1A ). This ligand-dependent coactivator/corepressor exchange results in transcriptional activation of genes involved in the control of adipogenesis and insulin action, as well as a diverse range of other functions that include fluid and electrolyte homeostasis, immune cell function, and bone homeostasis. In contrast to activating ligands, CPA was shown to stabilize the binding of the corepressor SMRT and to block TZD-stimulated adipogenesis and lipid accumulation in RAW macrophages. CPA has been detected in human serum by mass spectroscopy at concentrations of ∼10 nM (Shan et al., 2008Shan L. Li S. Jaffe K. Davis L. J. Chromatogr. A. 2008; 862: 161-167Google Scholar), but the mechanisms responsible for its production in mammalian cells remain poorly defined. Tsukahara et al., 2010Tsukahara T. Tsukahara R. Fujiwara Y. Yue J. Cheng Y. Guo H. Bolen A. Zhang C. Balazs L. Re F. et al.Mol. Cell. 2010; 39: 421-432Abstract Full Text Full Text PDF Scopus (93) Google Scholar provide evidence that CPA is produced from lysophosphatidylcholine (lyso-PC) dependent on phospholipase D2 (Figure 1B). Low-dose insulin and phorbol ester treatment of cells stimulate PLD2 activity, increase levels of CPA, and inhibit PPARγ activity. Although the production of CPA by PLD2 represents an unusual reaction product, and care must be taken to ensure that CPA is not artifactually produced by acid extraction (Shan et al., 2008Shan L. Li S. Jaffe K. Davis L. J. Chromatogr. A. 2008; 862: 161-167Google Scholar), the authors show that reduction of PLD2 expression reduces CPA accumulation and relieves PPARγ inhibition. TZDs have been shown to reduce carotid neointimal proliferation in patients with type 2 diabetes (Mazzone et al., 2006Mazzone T. Meyer P.M. Feinstein S.B. Davidson M.H. Kondos G.T. D'Agostino Sr., R.B. Perez A. Provost J.C. Haffner S.M. JAMA. 2006; 296: 2572-2581Crossref PubMed Scopus (588) Google Scholar), but direct application of the TZD rosiglitazone to the corotid artery wall of rats paradoxically induces neointimal proliferation (Cheng et al., 2009Cheng Y. Makarova N. Tsukahara R. Guo H. Shuyu E. Farrar P. Balazs L. Zhang C. Tigyi G. Cell. Signal. 2009; 21: 1874-1884Crossref Scopus (36) Google Scholar). Tsukahara and colleagues used this model to show that the proliferative effect of rosiglitazone could be blocked by coadministration of CPA, indicating that it can exert antagonistic effects in vivo. These observations raise numerous interesting questions for future investigation. In particular, it will be important to evaluate the production of CPA in relationship to that of endogenous agonists in tissues in which PPARγ plays important regulatory roles. Although there remains limited knowledge of relevant physiological PPARγ activators, a recently identified enzymatic pathway leading to production of 15-keto-PGE2 as an endogenous PPARγ agonist in adipocytes and colonic epithelial cells (Chou et al., 2007Chou W.L. Chuang L.M. Chou C.C. Wang A.H. Lawson J.A. FitzGerald G.A. Chang Z.F. J. Biol. Chem. 2007; 282: 18162-18172Crossref PubMed Scopus (67) Google Scholar, Harmon et al., 2010Harmon G.S. Dumlao D.S. Ng D.T. Barrett K.E. Dennis E.A. Dong H. Glass C.K. Nat. Med. 2010; 16: 313-318Crossref Scopus (75) Google Scholar) provides an instructive example for thinking about some of the possibilities. As illustrated in Figure 1B, production of CPA requires lyso PC as a substrate. This is generated by phospholipase A2 (PLA2) acting on phosphatidyl choline, which simultaneously liberates a polyunsaturated fatty acid (PUFA) from the sn-2 position of the glycerol backbone. These PUFAs then can serve as substrates for enzymes that generate PPARγ agonists, such as 15-keto-PGE2. PLA2, PLD2, and enzymes that potentially generate endogenous PPARγ agonists are all subject to signal-dependent control. It will be of considerable interest to determine whether alterations in these pathways lead to increased CPA production and contribute to a defect in PPARγ function that is reversed by TZD therapy. More generally, how is the production of agonist and antagonist balanced? By which intracellular mechanisms do cells monitor PPARγ activity? In addition to positive regulation of gene expression, anti-inflammatory activities of PPARγ have been suggested to contribute to antidiabetic activities of TZDs, particularly in macrophages (Odegaard et al., 2007Odegaard J.I. Ricardo-Gonzalez R.R. Goforth M.H. Morel C.R. Subramanian V. Mukundan L. Red Eagle A. Vats D. Brombacher F. Ferrante A.W. et al.Nature. 2007; 447: 1116-1120Crossref PubMed Scopus (1453) Google Scholar, Hevener et al., 2007Hevener A.L. Olefsky J.M. Reichart D. Nguyen M.T. Bandyopadyhay G. Leung H.Y. Watt M.J. Benner C. Febbraio M.A. Nguyen A.K. et al.J. Clin. Invest. 2007; 117: 1658-1669Crossref PubMed Scopus (384) Google Scholar). It will therefore be of interest to evaluate whether CPA is produced in macrophages and antagonizes the ability of PPARγ to suppress inflammatory responses. The potential roles of CPA in an inflammatory context are also relevant in light of the recent finding that PPARγ is phosphorylated at serine 273 in adipose tissue by Cdk5 in response to proinflammatory stimuli (Choi et al., 2010Choi J.H. Banks A.S. Estall J.L. Kajimura S. Bostrom P. Laznik D. Ruas J.L. Chalmers M.J. Kamenecka T.M. Bluher M. et al.Nature. 2010; 466: 451-456Crossref PubMed Scopus (630) Google Scholar). Serine 273 phosphorylation appears to impair the insulin-sensitizing activities of PPARγ disproportionately to its adipogenic activities that are dependent on classical ligand-dependent agonism. Intriguingly, TZDs and a selective PPARγ modulator that is a relatively poor classical agonist but retains antidiabetic activity inhibit S273 phosphorylation. This is not due to inhibition of Cdk5 itself, but rather appears to result from allosteric effects on PPARγ that alter its ability to serve as an effective Cdk5 substrate. These observations therefore raise the questions of whether CPA might have an opposite effect (i.e., make PPARγ a better substrate for Cdk5) and/or whether proinflammatory stimuli that induce Cdk5 activity might also lead to increased CPA production. Overall, these observations point to as-yet-uncharted aspects of PPARγ biology and the potential to differentially regulate its diverse activities by structurally distinct ligands. The identification of CPA as a naturally occurring PPARγ agonist opens up new avenues of investigation into mechanisms underlying insulin resistance, the molecular basis of the action of synthetic PPARγ agonists, and approaches to the development of improved antidiabetic and anti-inflammatory drugs. Phospholipase D2-Dependent Inhibition of the Nuclear Hormone Receptor PPARγ by Cyclic Phosphatidic AcidTsukahara et al.Molecular CellAugust 13, 2010In BriefCyclic phosphatidic acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARγ with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARγ target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Full-Text PDF Open Archive" @default.
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• W2073631244 title "A New Role for Cyclic Phosphatidic Acid as a PPARγ Antagonist" @default.
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