Jean Pierre SALLES - ?· Jean Pierre SALLES Unité d’Endocrinologie, Maladies Osseuses, Hôpital des…

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<ul><li><p>Lysophospholipides en physiopathologie </p><p> Jean Pierre SALLES </p><p>Unit dEndocrinologie, Maladies Osseuses, </p><p>Hpital des Enfants, </p><p>INSERM U 1043, CHU de Toulouse </p><p>InsermInserm</p></li><li><p>Kihara et al, Exp Cell Res. 2015 </p><p>Historique </p><p>+ Rcepteurs nuclaires: LPA, S1P </p></li><li><p>Varit des lysophospholipides </p><p>Makide et al, J. Lipid Res. 2014 </p><p>Concentrations variables dans les </p><p>liquides biologiques, lis lalbumine </p><p>(M) </p><p>Fraction libre ? </p><p>Contextes paracrines </p><p>Hydro-solubilit variable </p></li><li><p>Yanagida et al, BBA 2013 </p><p>Lysolipides homologues </p><p>trans-estrification </p><p>nantiomres </p><p>* * </p></li><li><p>Tigyi, Br. J. Pharmacol. 2010 </p><p>LPA6 </p><p>LPS </p></li><li><p>Makide et al, J. Lipid Res. 2014 </p><p>Rcepteurs des LPS </p></li><li><p>Yanagida et al, BBA 2013 </p><p>Slectivit des ligands </p><p> EDG receptors: LPA1-3 </p><p> smooth-muscle types </p><p>LPA1, LPA2: 1-acyl LPA </p><p>LPA3: : 2-acyl LPA </p><p>Non EDG receptors: LPA4-6 </p><p> platelet-like </p><p>LPA5: alkyl-LPA </p><p> Simon, Chap &amp; Douste-Blazy, BBRC </p><p>1982 </p><p>Gueguen et al, Biochemistry, 1999 </p><p> neuropathic pain </p><p>LPA6: 2-acyl LPA </p><p>(hypotrichose familiale) </p></li><li><p>Makide et al, J. Lipid Res. 2014 </p><p>Rcepteurs des LPS </p></li><li><p>LPI </p><p> Ca2+ </p><p>2-AG and LPI signaling </p><p>2-AG </p><p>cAMP </p><p>GPR55 CB1/CB2 LysoPLC </p><p>Gai Ga13 </p><p>Rcepteurs des LPI </p></li><li><p>2 rcepteurs pour les LPC ? </p><p>Jin-Yan et al, Nature Med. 2004 </p><p>Janusz et al, Science 2001 Zhu et al, J. Biol. Chem 2001 </p></li><li><p>2 rcepteurs pour les LPC ? </p><p>Jin-Yan et al, Nature Med. 2004 </p><p>Janusz et al, Science 2001 Zhu et al, J. Biol. Chem 2001 </p></li><li><p>Varit des rcepteurs des lysolipides </p><p>Choi &amp; Chun, BBA 2013 </p><p>LPA1: Gai, Gaq, </p><p>Ga12/13 </p><p>LPA4: Gas, Gaq, </p><p>Ga12/13 </p></li><li><p>Yung et al, Neuron 2015 </p><p>Intgration de laction du LPA </p></li><li><p>Lautotaxine: une lyso-PLC </p><p>Panchatcharam et al, BBA 2013 </p><p>Moolenaar et al, BBA 2013 </p></li><li><p>Intgration de laction du LPA </p><p>Yung et al, Neuron 2015 </p></li><li><p>PLC-RELATED LPA PRODUCTION </p><p>Production by platelets by PLC (thrombin) (Mauco &amp; Chap, 1978) </p><p>PLC, DAG kinase (Lapetina &amp; Siess, 1983) </p><p>PA hydrolysis by PLA2 ( Billah &amp; Lapetina, 1981) </p><p>PLA1 (Gerrard &amp; Robinson, 1989, Higgs &amp; Glomset, 1994, Inou &amp; </p><p>Okuyama, 1984, Arai et al, 2002) </p></li><li><p>external leaflet </p><p>internal leaflet </p><p>external leaflet </p><p>internal leaflet </p><p>Calcium </p><p>Cell transformation </p><p>Apoptosis </p><p>Microvesicles </p><p>sPLA2 </p><p>PA </p><p>PI, PA, PE </p><p>PI, PA, PE </p><p>PC </p><p>LPA </p><p>LPA PRODUCTION IN MEMBRANES </p></li><li><p>PA </p><p>PA sPLA2 </p><p>LPA </p><p>microvesicle </p><p>cell </p><p>PLC </p><p>Fourcade et al, Cell, 1995 </p><p>sPLA2 </p><p>LPA PRODUCTION INFLAMMATION </p></li><li><p>Infiltration </p><p>macrophagique/ostoclastique </p><p>ATX/LPA1 </p><p>LPA1 as a target for </p><p>inflammation </p><p>EXTENDED REPORT </p><p>Lysophosphatidic acid receptor inhibition as a new </p><p>multipronged treatment for rheumatoid arthritis </p><p>Miyabe et al, Arthritis Rheum. 2013 </p><p>Orosa et al. Ann Rheum Dis 2014 </p></li><li><p>Intgration de laction du LPA </p><p>Yung et al, Neuron 2015 </p></li><li><p>J. Lipid Res 2014 </p><p>Attnuation de leffet des ligands ( LPA, S1P) </p><p>LPP intracellulaires: mdiateurs intracellulaires (LPA, DAG) </p><p>Cibles thrapeutiques </p></li><li><p>Lysophosphatidyl phosphatases </p><p>Cellules msangiales rnales: </p><p>Effet trophique du LPA et S1P </p><p>Expression dune activit S1P </p><p>phosphatase faible densit </p><p>cellulaire </p><p>Gaits, Salles &amp; Chap, Kidney Int 1998 </p><p>Gennro et al, J. Biol. Chem 2002 </p><p>LPA et fibrose rnale </p><p>Pradere JP et al, J Am Soc. Nephrol. </p><p>2008 </p></li><li><p>Deficit en LPA-acyl transfrase </p><p>Lipo-atrophie gnralise (TG) </p><p>Rsistance linsuline +++ (AGL) </p><p>Syndrome acromgalique </p><p>taux trs leves de GHBP </p><p>Accumulation de LPA? </p><p>Clivage exagr du rcepteur de GH ? </p><p>Transactivation dune mtalloprotase ADAM Conte-Auriol et al, BBRC 2010 </p><p>LPA </p><p>Metallo protease </p><p>LPA R </p><p>GH receptor </p><p>Growth hormone binding protein </p><p>? </p><p>? </p><p>LPA </p></li><li><p>Yung et al, Neuron 2015 </p><p>Intgration de laction du LPA </p><p>Bone </p></li><li><p>cycle of remodeling in bone tissue </p><p>Osteocyte </p><p>RankL </p><p>osteoclast </p><p>Osteoblast </p><p>Proliferation </p><p>Differentiation </p><p>Resorption </p><p>Osteoblast </p><p>progenitor </p><p>Bone physiology </p><p>Osteoporosis </p><p>PTH </p><p>Gas </p><p>PTH </p><p>Gas </p><p>pelvis </p><p>femur </p></li><li><p>Dose and time dependence of LPA effect on alkaline phosphatase </p><p>0 </p><p>0,01 </p><p>0,02 </p><p>0,03 </p><p>0,04 </p><p>0 5 10 15 </p><p>C </p><p>OST </p><p>OST + LPA </p><p>LPA 10mM </p><p>AP</p><p> / A</p><p>DN</p><p> (n</p><p>mo</p><p>l / n</p><p>g / m</p><p>in) </p><p>Time (days) 0 </p><p>50 </p><p>100 </p><p>150 </p><p>200 </p><p>250 </p><p>0 0.1 0.5 1 5 10 </p><p>LPA (mM) </p><p>AP</p><p> (n</p><p>mo</p><p>l) </p><p>LPA </p><p>LPA + OST </p><p>CONT </p><p>OST </p><p>LPA </p><p>LPA </p><p>OST </p></li><li><p>LPA in bone </p><p>Sims et al , BBA 2013 </p></li><li><p>LPA and osteoclasts </p><p>Sims et al , BBA 2013 </p><p>* </p><p>LPA2 et osteoclasie </p></li><li><p>Boucharaba et al , J. Clin. Invest. 2004 </p><p>Boucharaba et al , PNAS 2004 </p><p>Peyruchaud et al, BBA 2013 </p></li><li><p>Gennero et al , Bone 2011 </p><p>Growth and bone phenotype of LPA1-invalidated mice </p></li><li><p>Gennero et al , Bone 2011 </p><p>LPA1-invalidated mice </p></li><li><p>LPA1-invalidated mice </p><p>Gennero et al , Bone 2011 </p><p>KO conditionnel ostoblastique (osterix) du LPA1 </p><p>(Gennero, Peyruchaud, Chun) </p></li><li><p>LPA4: a Gas-coupled receptor? </p><p>Liu et al , J. Cell. Biochem. 2010 </p><p>Invalidated Receptor BV/TV Conn. Dens Tb.N Tb.Th</p><p>LPA1 decreased Decreased decreased decreased</p><p>LPA4 increased increased increased increased</p><p>PTH/LPA4 </p><p>Gas/Ca++ </p><p>LPA1-Gai/Ca++ </p></li><li><p>Gas-mutated cells fail to differentiate </p><p>cAMP </p><p>osteoblasts </p><p>fibrous Cells </p><p> Mc Cune Albright syndrome, bone dysplasia </p></li><li><p>LPA1 in endochondral ossification </p><p>Salles et al , BBA 2013 </p></li><li><p>Lysolipids drug discovery </p></li><li><p>Rle pliotropique des Lysolipides en physiologie et en </p><p>pathologie </p><p>Possibilit de moduler leur effet par des antagonistes </p><p>spcifiques de rcepteurs </p><p> Importance du mtabolisme pour leur biodisponibilit </p><p>en grande partie paracrine </p><p>Essais thrapeutiques ouverts </p><p>Take home messages </p></li><li><p>INSERM UMR 1043 CNRS 5282 (CPTP) </p><p>Universit Toulouse Paul Sabatier </p><p>CHU de Toulouse </p><p>Isabelle Gennero </p><p>Sara Laurencin-Dalicieux </p><p>Franoise Conte-Auriol </p><p>Fabienne Briand-</p><p>Msange </p><p>Nicolas Beton </p><p>Hugues Chap </p><p>Maith Tauber </p><p>Jerold Chun </p><p>Scripps Inst., La Jolla, CA </p><p>Richard O.C. Oreffo </p><p>Southampton University, UK </p><p>Akira Tokumura </p><p>University of Tokushima, </p><p>JPN </p><p>Laurence Vico </p><p>INSERM U 590, Saint </p><p>Etienne, France </p><p>Olivier Peyruchaud </p><p>INSERM U 1088 </p><p>Lyon, France </p></li></ul>