The transport of cholesterol and triglycerides through the circulation occurs by way of lipoproteins. The triglyceride rich lipoproteins consist of chylomicrons, which arise from dietary fats, and very low density lipoproteins (VLDL), which come from de novo synthesis of triglycerides 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 resulting remnant particles are subsequently cleared by receptors in the liver, which include the low density lipoprotein receptor (Ldlr), low density lipoprotein-related protein-1 (Lrp1), and heparan sulfate proteoglycans. We recently showed that syndecan-1 is the major heparan sulfate proteoglycan receptor in the liver, and that it works in parallel to but independently of the other receptors on both intestinally-derived and hepatic lipoprotein particles. Current studies focus on factors that regulate syndecan-1 expression and turnover, structure-function studies of syndecan-1 and identification of the ligand on triglyceride-rich lipoproteins that bind to heparan sulfate.
In a separate project, we discovered that mutants lacking collagen XVIII, a type of heparan sulfate proteoglycan present in the basement membranes underlying endothelial cells, also accumulate plasma triglycerides and exhibit mild hyperchylomicronemia after fat feeding. Hypertriglyceridemia results from reduced presentation of lipoprotein lipase on the lumenal surface of the endothelium and delayed lipolysis in the peripheral circulation. This is the first report showing that triglyceride-rich lipoprotein metabolism in vivo can be affected, albeit indirectly, by a basement membrane proteoglycan. We also showed that humans with Knobloch Syndrome, caused by a null mutation in the heparan sulfate proteoglycan Type XVIII collagen, also exhibit fasting hypertriglyceridemia, a previously unrecognized phenotype in these patients.
We are also interested in the function of macrophage proteoglycans. Genetically altering heparan sulfate proteoglycans in macrophages led to unexpectedly striking effects on atherosclerosis, increasing plaque size in animals fed a Western high fat diet. Both the number of macrophages and their propensity to convert to foam cells is greatly enhanced, suggesting that proteoglycans normally serve an atheroprotective role. Current studies are focused on the interaction of the proteoglycans with receptors on the macrophage that modulated activation of the cells.