title: Increased atherosclerosis in P2Y13/apolipoprotein E double-knockout mice: contribution of P2Y13 to reverse cholesterol transport.
abstract: OBJECTIVE
  High-density lipoproteins (HDLs) protect against atherosclerosis mainly due to their function in hepatobiliary reverse cholesterol transport (RCT). This is a process whereby excess cholesterol from peripheral tissues is transported by HDL particles to the liver for further metabolism and biliary excretion. Hepatic uptake of HDL holoparticles involves the P2Y13 receptor, independently of the selective cholesteryl ester uptake mediated by scavenger receptor class B, type I (SR-BI). Accordingly, P2Y13-deficient mice (P2Y13 (-/-)) have impaired RCT. This study assessed whether P2Y13 deficiency would affect atherosclerotic development.
  
  
  RESULTS
  P2Y13 (-/-) mice were crossbred with atherosclerosis-prone apoE(-/-) mice. When 15 weeks old, P2Y13 (-/-)/apoE(-/-) mice had more aortic sinus lesions than apoE(-/-) mice. Bone marrow transplantation showed that the absence of the P2Y13 receptor in blood cells did not lead to significantly greater atherosclerotic plaque size formation compared with control apoE(-/-) reconstituted animals. Conversely, the absence of the P2Y13 receptor, except in blood cells, resulted in lesion sizes similar to that in P2Y13 (-/-)/apoE(-/-) reconstituted mice, pointing to a role for non-haematopoietic-derived P2Y13. Unexpectedly, P2Y13 (-/-)/apoE(-/-) mice displayed a lower HDL-cholesterol level than apoE(-/-) mice, which might be due to greater SR-BI expression in the liver. However, P2Y13 deficiency in apoE(-/-) mice was translated into reduced biliary and faecal sterol excretion and impaired RCT from macrophage to faeces, suggesting that an alteration in hepatobiliary RCT could be solely responsible for the greater atherosclerosis observed.
  
  
  CONCLUSIONS
  The P2Y13 receptor protects against atherosclerosis, primarily through its role in hepatobiliary RCT.
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France.
authors.forename: Laeticia
authors.initials: L
authors.lastname: Lichtenstein
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France.
authors.forename: Nizar
authors.initials: N
authors.lastname: Serhan
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Espinosa-Delgado
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fabre
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Wijtske
authors.initials: W
authors.lastname: Annema
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.affiliation: Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.affiliation: Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Laffargue
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France CHU de Toulouse, Hôpital Purpan, Toulouse, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Perret
authors.affiliation: INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, France Université de Toulouse III, UMR 1048, Toulouse, France CHU de Toulouse, Hôpital Purpan, Toulouse, France INSERM U1048, Bât. L3, Hôpital Rangueil, BP 84225, 31432 Toulouse cedex 04, France laurent.martinez@inserm.fr.
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Martinez
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics; D004195:Disease Models, Animal; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; C486689:P2ry13 protein, mouse; D018048:Receptors, Purinergic P2
keywords: ATP synthase; Bile acids; Cholesterol; High-density lipoprotein; Purinergic receptor