Lipoproteins

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 structure-function studies of syndecan-1 and characterization of apolipoproteins that modulate binding of lipoproteins to the various receptors.

An important finding that emerged from our 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-beta. 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 variation in heparan sulfate content or structure in hepatocytes and macrophages could result in differential susceptibility to hyperlipidemia and cardiovascular disease.

Relevant Papers

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.

Goulbourne, C.N., Gin, P., Tatar, A., Nobumori, C., Hoenger, A., Jiang, H., Grovenor, C.R., Adeyo, O., Esko, J.D., Goldberg, I.J., Reue, K., Tontonoz, P., Bensadoun, A., Beigneux, A.P., Young, S.G., and Fong, L.G. (2014 ) The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell Metab. 19:849-860.

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.

Gordts, P.L., Nock, R., Son, N.H., Ramms, B., Lew, I., Gonzales, J.C., Thacker, B.E., Basu, D., Lee, R.G., Mullick, A.E., Graham, M.J., Goldberg, I.J., Crooke, R.M., Witztum, J.L. and Esko, J.D. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J. Clin. Invest. 26:2855-2866.