P2Y13 receptor is critical for reverse cholesterol transport.
A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote "reverse cholesterol transport" (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y(13) (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y(13) as a target to promote RCT has not been documented. Here, we show that P2Y(13)-deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y(13)-deficient mice. Furthermore, cangrelor, a partial agonist of P2Y(13), stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BI-knockout(liver)) but had no effect in P2Y(13) knockout mice, which indicate that P2Y(13)-mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake.


CONCLUSIONS
These results establish P2Y(13) as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT.
Fabre
Aurélie C
AC
Institut National de la Santé et de la Recherche Médicale (INSERM), Unit 563, Toulouse, France.
Malaval
Camille
C
Ben Addi
Abduelhakem
A
Verdier
Céline
C
Pons
Véronique
V
Serhan
Nizar
N
Lichtenstein
Laeticia
L
Combes
Guillaume
G
Huby
Thierry
T
Briand
François
F
Collet
Xavier
X
Nijstad
Niels
N
Tietge
Uwe J F
UJ
Robaye
Bernard
B
Perret
Bertrand
B
Boeynaems
Jean-Marie
JM
Martinez
Laurent O
LO
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000502:physiology*; D051122:Scavenger Receptors, Class B / Q000172:deficiency
D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; C486689:P2ry13 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D000249:Adenosine Monophosphate; C117446:cangrelor; D002784:Cholesterol