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.