Heparan sulfate proteoglycans present PCSK9 to the LDL receptor

Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9: LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease

Nitrate reduction in geologically heterogeneous catchments:a framework for assessing the scale of predictive capability of hydrological models

International audienceIn order to fulfil the requirements of the EU Water Framework Directive nitrate load from agricultural areas to surface water in Denmark needs to be reduced by about 40%. The regulations imposed until now have been uniform, i.e. the same restrictions for all areas independent of the subsurface conditions. Studies have shown that on a national basis about 2/3 of the nitrate leaching from the root zone is reduced naturally, through denitrification, in the subsurface before reaching the streams. Therefore, it is more cost-effective to identify robust areas, where nitrate leaching through the root zone is reduced in the saturated zone before reaching the streams, and vulnerable areas, where no subsurface reduction takes place, and then only impose regulations/restrictions on the vulnerable areas. Distributed hydrological models can make predictions at grid scale, i.e. at much smaller scale than the entire catchment. However, as distributed models often do not include local scale hydrogeological heterogeneities, they are typically not able to make accurate predictions at scales smaller than they are calibrated. We present a framework for assessing nitrate reduction in the subsurface and for assessing at which spatial scales modelling tools have predictive capabilities. A new instrument has been developed for airborne geophysical measurements, Mini-SkyTEM, dedicated to identifying geological structures and heterogeneities with horizontal and lateral resolutions of 30-50 m and 2 in, respectively, in the upper 30 m. The geological heterogeneity and uncertainty are further analysed by use of the geostatistical software TProGS by generating stochastic geological realisations that are soft conditioned against the geophysical data. Finally, the flow paths within the catchment are simulated by use of the MIKE SHE hydrological modelling system for each of the geological models generated by TProGS and the prediction uncertainty is characterised by the variance between the predictions of the different models. (C) 2013 Elsevier B.V. All rights reserved