Lipoproteins
Lipoproteins are particles that transport cholesterol and triglycerides, through the circulation for delivery to cells. The triglyceride rich lipoproteins consist of chylomicrons, which arise from dietary fats, and very low density lipoproteins (VLDL), which come from de novo synthesis in the liver Lipoprotein lipase (LPL) acts on these particles to generate free fatty acids for energy production in the heart and skeletal muscles and for storage in adipose tissue. The remnant particles are further acted on by hepatic lipase (HL) in the liver sinusoids, and are subsequently cleared by receptors in the liver, which recognize the apolipoproteins, apoB and apoE, or bound lipases. Heparan sulfate binds to several proteins important to lipoprotein metabolism, including apoB, apoE, LPL, and HL.
To study the role of hepatic heparan sulfate, we altered the expression of the biosynthetic gene GlcNAc 
N-deacetylase/N-sulfotransferase (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in ~50% reduction of sulfation of liver heparan sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles resembling chylomicron remnants and VLDL. Mutant mice synthesized VLDL normally, but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared to mice lacking only LDL receptors, suggesting that heparan sulfate participatesin the clearance of cholesterol-rich lipoproteins as well. Post-prandial studies showed that clearance of intestinally derived lipoproteins also depends on hepatocyte heparan sulfate.
These findings show that under normal physiological conditions hepatic heparan sulfate proteoglycans work in parallel with LDL receptors to clear both intestinally-derived and hepatic lipoprotein particles. Current studies focus on the individual proteoglycans that modulate lipoprotein metabolism and the mechanism by which proteoglycans mediate clearance and metabolism. We are also interested in genetic variation in the human population in genes encoding the proteoglycan core proteins and the biosynthetic enzymes involved in heparan sulfate.