Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing.
Unraveling the mechanisms controlling remnant lipoprotein clearance is important, as these lipoproteins are highly atherogenic. The most critical molecule in this process is apoE, which mediates high-affinity binding of remnant lipoproteins to members of the LDL receptor (LDLR) family and cell-surface heparan sulfate proteoglycans (HSPGs), which have been shown to play major independent as well as cooperative roles in remnant lipoprotein clearance. While all the players may have been identified, our understanding of how they interact and function together continues to evolve. In this issue of the JCI, MacArthur et al. (see the related article beginning on page 153) demonstrated that HSPGs under normal physiological conditions are critically important in the clearance of remnant lipoproteins, independent of LDLR family members. The complexity of VLDL and chylomicron remnant clearance was exemplified by the studies of Jones et al., also in this issue (see the related article beginning on page 165). Despite defective clearance of LDL in mice with a deficiency in the adaptor protein controlling internalization of the LDLR, called autosomal recessive hypercholesterolemia (ARH), remnant lipoprotein clearance was not grossly abnormal. A likely explanation is that the abnormal LDLRs bind the remnants and then transfer them to another acceptor for internalization. While the studies clearly demonstrate that the LDLR-related protein 1 is not involved and suggest a role for an additional unidentified receptor, it remains a possibility that HSPGs are responsible for remnant uptake by hepatocytes in the presence of defective LDLR internalization.
Mahley
Robert W
RW
Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA. rmahley@gladstone.ucsf.edu
Huang
Yadong
Y
D050197:Atherosclerosis / Q000503:physiopathology* / Q000517:prevention & control; D001692:Biological Transport; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D008954:Models, Biological; D011509:Proteoglycans / Q000378:metabolism / Q000493:pharmacokinetics / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
D019812:Heparan Sulfate Proteoglycans; D008074:Lipoproteins; D011509:Proteoglycans; D011973:Receptors, LDL; D014280:Triglycerides