[Show abstract][Hide abstract] ABSTRACT: Cell surface receptors for high-density lipoprotein (HDL) on hepatocytes are major partners in the regulation of cholesterol homeostasis. We recently identified a cell surface ATP synthase as a high-affinity receptor for HDL apolipoprotein A-I (apoA-I) on human hepatocytes. Stimulation of this ectopic ATP synthase by apoA-I triggered a low-affinity-receptor-dependent HDL endocytosis by a mechanism strictly related to the generation of ADP. This suggests that nucleotide G-protein-coupled receptors of the P2Y family are molecular components in this pathway. Only P2Y1 and P2Y13 are present on the membrane of hepatocytes. Using both a pharmacological approach and small interference RNA, we identified P2Y13 as the main partner in hepatic HDL endocytosis, in cultured cells as well as in situ in perfused mouse livers. We also found a new important action of the antithrombotic agent AR-C69931MX as a strong activator of P2Y13-mediated HDL endocytosis.
Full-text · Article · Dec 2005 · Cellular and Molecular Life Sciences CMLS
[Show abstract][Hide abstract] ABSTRACT: Several large prospective studies have established that HDL-cholesterol is an independent negative risk factor, for coronary heart disease and thus represents today a major protective factor against atherosclerosis. The HDL exert pleiotropic effects, such as anti-inflammatory, antithrombotic and antioxydant properties, associated with their protective role. This protective effect of the HDL is mostly attributed to the central function of these lipoproteins in reverse cholesterol transport (RCT), a process whereby excess cell cholesterol is taken up and esterified within the HDL, then brought back to the liver before being excreted in the bile, in the form of free cholesterol or after transformation into biliary acids. This process relies on specific interactions between the HDL particles and cells, on the one hand peripheral (cholesterol efflux) and on the other hepatic (HDL-cholesterol disposal), and on the maturation of HDL-particles in the vascular compartment. Among cellular proteins interacting with the HDL, some contribute to the formation of the HDL - cellular transporter ABCA1 (ATP-binding cassette transporter A1), for example - whereas others are involved in HDL catabolism, Scavenger Receptor-class B type I (SR-BI) or cell surface ATP-synthase/hydrolase, recently described at the surface of the hepatocytes. During the last decade, considerable breakthroughs were made in the identification and the comprehension of the role of cellular proteins involved in HDL metabolism and in their transcriptional regulations, opening new perspectives for the modulation of HDL-cholesterol. Moreover, some genetic variants were described, and others will be probably discovered, which could help explain inter-individual variance of the levels of HDL.
No preview · Article · Jan 2005 · Sang Thrombose Vaisseaux
[Show abstract][Hide abstract] ABSTRACT: High-density lipoprotein (HDL) cholesterol is an independent negative risk factor for coronary artery disease and thus represents today the only protective factor against atherosclerosis. The protective effect of HDL is mostly attributed to its central function in reverse cholesterol transport (RCT), a process whereby excess cell cholesterol is taken up and processed in HDL particles, and is later delivered to the liver for further metabolism and bile excretion. This process relies on specific interactions between HDL particles and cells, both peripheral (cholesterol efflux) and hepatic (cholesterol disposal) cells, and on the maturation of HDL particles within the vascular compartment. The plasma level of HDL cholesterol will thus result also from the complex interplay with cellular partners. Among them, some contribute to HDL formation - for instance ATP binding cassette AI protein - while others are mostly involved in HDL catabolism, the scavenger receptor-class B type I or the recently described membrane-bound ATP synthase/hydrolase. The last decade has seen major breakthroughs in the identification and elucidation of the role of cellular partners of HDL metabolism, and in their transcriptional regulations, opening up new perspectives in the modulation of HDL cholesterol.
No preview · Article · Oct 2004 · Cellular and Molecular Life Sciences CMLS
[Show abstract][Hide abstract] ABSTRACT: The effect of high-density lipoprotein (HDL) in protecting against atherosclerosis is usually attributed to its role in 'reverse cholesterol transport'. In this process, HDL particles mediate the efflux and the transport of cholesterol from peripheral cells to the liver for further metabolism and bile excretion. Thus, cell-surface receptors for HDL on hepatocytes are chief partners in the regulation of cholesterol homeostasis. A high-affinity HDL receptor for apolipoprotein A-I (apoA-I) was previously identified on the surface of hepatocytes. Here we show that this receptor is identical to the beta-chain of ATP synthase, a principal protein complex of the mitochondrial inner membrane. Different experimental approaches confirm this ectopic localization of components of the ATP synthase complex and the presence of ATP hydrolase activity at the hepatocyte cell surface. Receptor stimulation by apoA-I triggers the endocytosis of holo-HDL particles (protein plus lipid) by a mechanism that depends strictly on the generation of ADP. We confirm this effect on endocytosis in perfused rat liver ex vivo by using a specific inhibitor of ATP synthase. Thus, membrane-bound ATP synthase has a previously unsuspected role in modulating the concentrations of extracellular ADP and is regulated by a principal plasma apolipoprotein.