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.

Relevant Papers

    Stanford, K.I., Bishop, J.R., Foley, E.M., Gonzales, J.C., Niesman, I.R., Witztum, J.L. and Esko, J.D. (2009) Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in vivo. J. Clin. Invest. 119:3236-3245

    Bishop, J.R., Passos-Bueno, M.R., Fong, L., Stanford, K.I., Gonzales, J.C., Yeh, E., Young, S.G., Bensadoun, A., Witztum, J.L., Esko, J.D., Moulton, K.S. (2010) Deletion of the basement membrane heparan sulfate proteoglycan Type XVIII collagen causes hypertriglyceridemia in mice and humans. PLoS One. 5:e13919

    Deng, Y.*, Foley, E.M.*, Gonzales, J.C.*, Gordts, P.L., Li, Y., Esko, J.D. (2011) Shedding of syndecan-1 from human hepatocytes alters VLDL clearance. Hepatology 55:277-86

    Gonzales, J.C.*, Gordts, P.L., Foley, E.M.* and Esko, J.D. (2013) Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J. Clin Invest., 23:2742-2751.

    Foley, E.M.*, Gordts, P.L., Stanford, K.I.*, Gonzales, J.C.*, Lawrence, R., Stoddard, N.* and Esko, J.D. (2013) Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol. 33:2065-2074.

    Gordts, P.L.S.M., Foley, E., Lawrence, R., Sinha, R., Lameda-Diaz, C., Deng,, L., Nock, R. Glass, C.K., Erbilgin, A., Lusis, A.J., Witztum, J.L. and Esko, J.D. (2014) Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced Type I interferon signaling. Cell Metab. In press.