Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.
The plasma clearance of intestinally derived remnant lipoproteins by the liver is a process that likely involves three steps. Our model suggests that the initial rapid clearance by the liver begins with sequestration of the remnants within the space of Disse, where apolipoprotein E secreted by hepatocytes 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 Disse by hepatic and lipoprotein lipases, which may also serve as ligands mediating remnant uptake. The final step, endocytosis by hepatocytes, appears to be mediated, at least in part, by the low density lipoprotein (LDL) receptor and by the LDL receptor-related protein (LRP). Cell-surface HSPG play a critical role in remnant uptake, not only in the important initial sequestration or capture step in the space of Disse, but also as an essential or integral component of the HSPG-LRP pathway. In addition, HSPG appear to function alone as a receptor and display unique handling properties for specific isoforms of apolipoprotein E.
Mahley
R W
RW
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94141-9100, USA.
Ji
Z S
ZS
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001693:Biological Transport, Active; D002462:Cell Membrane / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D004705:Endocytosis; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D006952:Hyperlipoproteinemia Type III / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism
D001057:Apolipoproteins E; D002914:Chylomicrons; D019812:Heparan Sulfate Proteoglycans; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D008049:Lipase; D008071:Lipoprotein Lipase