Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E

The plasma clearance of intestinally derived remnant lipoproteins by the li ver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the r emnants within the space of Disse, where apolipoprotein E secreted by hepat ocytes enhances remnant binding and uptake, Heparan sulfate proteoglycans ( HSPG), which are also abundant in the space of Disse, mediate this enhanced binding, Next, the remnants undergo further processing in the space of Dis se by hepatic and lipoprotein lipases, which may also serve as ligands medi ating remnant uptake. The final step, endocytosis by hepatocytes, appears t o be mediated, at least in part, by the low density lipoprotein (LDL) recep tor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequest ration or capture step in the space of Disse, but also as an essential or i ntegral component of the HSPG-LRP pathway. In addition, HSPG appear to func tion alone as a receptor and display unique handling properties for specifi c isoforms of apolipoprotein E.