Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion
| Autor: | Laeticia Lichtenstein, Nicole Malet, Bertrand Perret, Nizar Serhan, Céline Verdier, Cendrine Cabou, Muriel Laffargue, Laurent O. Martinez |
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| Přispěvatelé: | Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de pharmacie, Faculté de Pharmacie de Toulouse |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
MESH: Biological Transport Cell MESH: Bile Acids and Salts [SDV.BC]Life Sciences [q-bio]/Cellular Biology 030204 cardiovascular system & hematology Biology Partial agonist MESH: Lipoproteins HDL Bile Acids and Salts Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cangrelor Internal medicine medicine Animals MESH: Receptors Purinergic P2 MESH: Animals MESH: Adenosine Monophosphate Receptor Molecular Biology [SDV.BC] Life Sciences [q-bio]/Cellular Biology MESH: Mice 030304 developmental biology 0303 health sciences Receptors Purinergic P2 Cholesterol Cholesterol HDL Reverse cholesterol transport Biological Transport Cell Biology Metabolism Adenosine Monophosphate 3. Good health medicine.anatomical_structure Endocrinology Liver chemistry MESH: Purinergic P2Y Receptor Agonists lipids (amino acids peptides and proteins) Purinergic P2Y Receptor Agonists MESH: Cholesterol HDL Lipoproteins HDL Flux (metabolism) MESH: Liver |
| Zdroj: | BBA-Biochimica et Biophysica Acta BBA-Biochimica et Biophysica Acta, 2013, 1831 (4), pp.719-25. ⟨10.1016/j.bbalip.2012.12.006⟩ BBA-Biochimica et Biophysica Acta, Elsevier, 2013, 1831 (4), pp.719-25. ⟨10.1016/j.bbalip.2012.12.006⟩ |
| ISSN: | 0006-3002 |
| DOI: | 10.1016/j.bbalip.2012.12.006 |
| Popis: | International audience; High level of high-density lipoprotein cholesterol (HDL-cholesterol) is inversely correlated to the risk of atherosclerotic cardiovascular disease. The protective effect of HDL is mostly attributed to their metabolic functions in reverse cholesterol transport (RCT), a process whereby excess cell cholesterol is taken up from peripheral cells and processed in HDL particles, and is later delivered to the liver for further metabolism and bile excretion. We have previously demonstrated that P2Y13 receptor is critical for RCT and that intravenous bolus injection of cangrelor (AR-C69931MX), a partial agonist of P2Y13 receptor, can stimulate hepatic HDL uptake and subsequent lipid biliary secretion without any change in plasma lipid levels. In the present study, we investigated the effect of longer-term treatment with cangrelor on lipoprotein metabolism in mice. We observed that continuous delivery of cangrelor at a rate of 35μg/day/kg body weight for 3days markedly decreased plasma HDL-cholesterol level, by increasing the clearance of HDL particles by the liver. These effects were correlated to an increase in the rate of biliary bile acid secretion. An increased expression of SREBP-regulated genes of cholesterol metabolism was also observed without any change of hepatic lipid levels as compared to non-treated mice. Thus, 3-day cangrelor treatment markedly increases the flux of HDL-cholesterol from the plasma to the liver for bile acid secretion. Taken together our results suggest that P2Y13 appears a promising target for therapeutic intervention aimed at preventing or reducing cardiovascular risk. |
| Databáze: | OpenAIRE |
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