P2Y13 receptor is critical for reverse cholesterol transport
| Autor: | Laurent O. Martinez, Véronique Pons, Xavier Collet, François Briand, Céline Verdier, Guillaume Combes, Bernard Robaye, Bertrand Perret, Jean-Marie Boeynaems, Thierry Huby, Abduelhakem Ben Addi, Aurélie C.S. Fabre, Camille Malaval, Uwe J. F. Tietge, Nizar Serhan, Niels Nijstad, Laeticia Lichtenstein |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM) |
| Rok vydání: | 2010 |
| Předmět: |
Purinergic P2 Receptor Agonists
EXPRESSION HDL ENDOCYTOSIS medicine.medical_specialty LIVER ABCA1 chemistry.chemical_compound High-density lipoprotein Internal medicine medicine Animals Scavenger receptor Receptor Mice Knockout Hepatology biology Receptors Purinergic P2 Cholesterol Cholesterol HDL Reverse cholesterol transport Purinergic receptor Biological Transport Scavenger Receptors Class B Adenosine Monophosphate MICE Endocrinology chemistry biology.protein Cholesteryl ester SELECTIVE UPTAKE SECRETION BILE lipids (amino acids peptides and proteins) Lipoproteins HDL HIGH-DENSITY-LIPOPROTEIN |
| Zdroj: | Hepatology, 52(4), 1477-1483. Wiley |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.23897 |
| Popis: | 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. Conclusion: 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. (HEPATOLOGY 2010;52:1477-1483) |
| Databáze: | OpenAIRE |
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