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Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion.
Serhan, Nizar; Cabou, Cendrine; Verdier, Céline; Lichtenstein, Laeticia; Malet, Nicole; Perret, Bertrand; Laffargue, Muriel; Martinez, Laurent O.
Afiliación
  • Serhan N; INSERM, UMR 1048, Institut de Maladies Métaboliques et Cardiovasculaires, Toulouse, 31000, France.
Biochim Biophys Acta ; 1831(4): 719-25, 2013 Apr.
Article en En | MEDLINE | ID: mdl-23266391
ABSTRACT
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ácidos y Sales Biliares / Receptores Purinérgicos P2 / HDL-Colesterol / Hígado Límite: Animals Idioma: En Revista: Biochim Biophys Acta Año: 2013 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Ácidos y Sales Biliares / Receptores Purinérgicos P2 / HDL-Colesterol / Hígado Límite: Animals Idioma: En Revista: Biochim Biophys Acta Año: 2013 Tipo del documento: Article País de afiliación: Francia