Lipoprotein Model

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 ligands on triglyceride-rich lipoproteins that bind to heparan sulfate.

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.

An important finding that emerged from these studies is that subtle changes in heparan sulfate composition can have profound effects on lipoprotein binding and clearance in the liver and on macrophage activation by interferon-b. We also showed that naturally occurring heterozygous mutations in EXT1, which encodes the copolymerase required for heparan sulfate assembly, results in post-prandial hypertriglyceridemia. Interestingly, natural variation exists in plasma and leukocyte heparan sulfate composition as noted in studies of small cohorts of normal individuals. One of our aims is to study how natural variation in heparan sulfate content or structure in hepatocytes and macrophages could result in differential susceptibility to hyperlipidemia and cardiovascular disease.

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

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. 20, 813–826. Highlighted in: N. R. Gough (2014) Heparan sulfate proteoglycans control basal inflammation. Sci. Signal. 7, ec320.

Mooij, H.L., Bernelot Moens, S.J., Gordts, P.L., Stanford, K.I., Foley, E.M., van den Boogert, M.A., Witjes, J.J., Hassing, H.C., Tanck, M.W., van de Sande, M.A., Levels, J.H., Kastelein, J.J., Stroes, E.S., Dallinga-Thie, G.M., Esko, J.D. and Nieuwdorp, M. (2015) Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. J. Lipid Res. 56:665-673.