Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis

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.     

The role of cysteine in the detoxification of an herbicide]

The methyl 2-chloro-3 (4-chlorophenyl) propionate is quickly hydrolysed through coleoptiles of wheat (coleoptile test). Then, depending on the concentration of the compounds, one observes mainly a further degradation (at 0,01 mM) of the acid or conjugation (at 0,1 mM) of it with cystein in vivo. This second type of physiological neutralisation appears to be more efficient than the catabolism which give derivatives of benzoic acid.     

A probable stellar solution to the cosmological lithium discrepancy

The measurement of the cosmic microwave background has strongly constrained the cosmological parameters of the Universe. When the measured density of baryons (ordinary matter) is combined with standard Big Bang nucleosynthesis calculations, the amounts of hydrogen, helium and lithium produced shortly after the Big Bang can be predicted with unprecedented precision. The predicted primordial lithium abundance is a factor of two to three higher than the value measured in the atmospheres of old stars. With estimated errors of 10 to 25%, this cosmological lithium discrepancy seriously challenges our understanding of stellar physics, Big Bang nucleosynthesis or both. Certain modifications to nucleosynthesis have been proposed, but found experimentally not to be viable. Diffusion theory, however, predicts atmospheric abundances of stars to vary with time, which offers a possible explanation of the discrepancy. Here we report spectroscopic observations of stars in the metal-poor globular cluster NGC 6397 that reveal trends of atmospheric abundance with evolutionary stage for various elements. These element-specific trends are reproduced by stellar-evolution models with diffusion and turbulent mixing. We thus conclude that diffusion is predominantly responsible for the low apparent stellar lithium abundance in the atmospheres of old stars by transporting the lithium deep into the star.     

A Review on Complex System Engineering

Journal of Systems Science and Complexity - Complexity is commonly summarized as ‘the actions of the whole are more than the sum of the actions of the parts’. Understanding how the...     

The nucleotide receptor P2Y13 is a key regulator of hepatic High-Density Lipoprotein (HDL) endocytosis

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. Received 9 May 2005; received after revision 24 June 2005; accepted 1 September 2005     

From α, β-Epoxyaldehydes to Peptidonucleosides and Iminosugars

The primary objectives of the group “Natural products and bioactive molecules”, are the development of synthetic methods, their application in the elaboration of natural compounds and analogues and the translation of this know-how through an integrated approach to the identification of attractive leads in order to confront some of the major diseases in the developed and developing countries.     

Cell surface adenylate kinase activity regulates the F1-ATPase/P2Y13-mediated HDL endocytosis pathway on human hepatocytes

We have previously demonstrated on human hepatocytes that apolipoprotein A-I binding to an ecto-F₁-ATPase stimulates the production of extracellular ADP that activates a P2Y₁₃-mediated high-density lipoprotein (HDL) endocytosis pathway. Therefore, we investigated the mechanisms controlling the extracellular ATP/ADP level in hepatic cell lines and primary cultures to determine their impact on HDL endocytosis. Here we show that addition of ADP to the cell culture medium induced extracellular ATP production that was due to adenylate kinase and nucleoside diphosphokinase activities, but not to ATP synthase activity. We further observed that in vitro modulation of both ecto-NDPK and AK activities could regulate the ADP-dependent HDL endocytosis. But interestingly, only AK appeared to naturally participate in the pathway by consuming the ADP generated by the ecto-F₁-ATPase. Thus controlling the extracellular ADP level is a potential target for reverse cholesterol transport regulation. Received 13 July 2006; received after revision 29 August 2006; accepted 19 September 2006