Lipoprotein clearance: Grabbed by glycans

Lipidomics Gateway (30 December 2009) [doi:10.1038/lipidmaps.2009.37]

The heparan sulfate proteoglycan syndecan-1 mediates hepatic clearance of triglyceride-rich lipoproteins in vivo.

This article appeared on the Functional Glycomics Gateway doi:10.1038/fg.2009.38

Heparan sulfate proteoglycans have many roles in cell physiology. From: Bishop, J. R. et al. Nature 446, 1030-1037 (2007) doi:10.1038/nature05817

Remnant lipoproteins are cleared from the blood by endocytic receptors in the liver, including the low density lipoprotein receptor (LDLR) and heparan sulfate proteoglycans (HSPGs). The HSPG syndecan-1, and the degree of HSPG sulfation, have both been implicated in lipoprotein binding. However, the relevant HSPG in the liver, the specific sulfate requirements, and whether HSPGs internalize lipoproteins directly or require another receptor have all been unclear. Two papers from Jeff Esko and colleagues, in the Journal of Clinical Investigation and the Journal of Biological Chemistry, now show that syndecan-1, independent of LDLR, is the relevant hepatic HSPG for clearance of triglyceride-rich lipoproteins (TRLs) in mice, and that clearance depends on specific subclasses of sulfate groups rather than the overall charge. These findings might help to explain some human cases of hypertriglyceridemia.

TRLs in the blood derive either from dietary fats (chylomicrons) or newly synthesized lipids (very low density lipoprotein, VLDL). Lipoprotein lipase hydrolyses TRLs, liberating lipids for uptake by tissues, and remnant TRLs are cleared from the circulation in the liver. Hypertriglyceridemia – a facet of metabolic syndrome and implicated in atherosclerosis – can result from insufficient clearance. HSPGs are implicated in TRL clearance by in vitro and cell culture studies, and are known to function as endocytic receptors for various ligands. Esko and colleagues measured plasma triglyceride and fasting plasma lipoprotein levels in syndecan-1 knockout (Sdc1^-/- ) mice, observing accumulation of triglycerides and delayed clearance of TRLs. A mutation that affects sulfation of heparan sulfate chains on all HSPGs and also leads to delayed TRL clearance did not compound the effect of syndecan-1 deficiency, indicating that other HSPGs are unlikely to be involved. This also causally implicates the heparan sulfate chains of syndecan-1 to the hyperlipidemia of the Sdc1^-/- mice.

In their second study, the authors addressed the specific contribution of HSPG sulfate groups to delayed TRL clearance. They generated a hepatocyte-selective knockout of a gene that controls 2-O-sulfation of heparan sulfate uronic acid residues. The reduction in 2-O-sulfation produced an increase in N-sulfation and 6-O-sulfation, but nevertheless resulted in accumulation of triglycerides in the mutant, and reduced VLDL uptake in isolated hepatocytes. Further, inactivation of 6-O-sulfation did not increase plasma triglycerides. Heparin, which is more highly sulfated than heparan sulfate, blocked uptake of VLDL by isolated hepatocytes and this depended on the presence of 2-O-sulfation but not 6-O-sulfation. These data indicate that specific sulfate modifications and not the overall degree of sulfation are critical for TRL clearance by HSPGs.

The mechanism of internalization of ligands by HSPGs is still unclear and it is also unknown how reducing one class of sulfation on heparan sulfate leads to an increase in other classes. The precise HSPG ligand or ligands within lipoproteins is also undefined. However, these studies show that 2-O-sulfated syndecan-1 mediates hepatic TRL clearance, and offer a new avenue to explore for unexplained cases of hypertriglyceridemia.

Emma Leah