Genetic Analysis of Proteoglycan-Mediated Lipoprotein Clearance. Hypertriglyceridemia results from the accumulation of triglyceride-rich lipoproteins (TRLs) in the circulation (chylomicrons, very low-density lipoproteins, and their remnants). Because patients with hypertriglyceridemia have increased risk for atherosclerosis and coronary artery disease, considerable interest exists in understanding its etiology and therapy. TRL accumulation can arise from altered lipid biosynthesis, apolipoproteinemias, and alterations in lipolysis in the peripheral circulation. It can also arise from defective clearance of lipoprotein remnants in the liver, which occurs through a multi-step process involving sequestration of remnant lipoproteins in the space of Disse and receptor-mediated endocytosis by hepatocytes. Hepatocytes express several receptors, including members of the LDL receptor family and Syndecan-1 (Sdc1), a trans-membrane heparan sulfate proteoglycan. Studies of Sdc1-deficient mice showed that Sdc1 is the primary proteoglycan receptor that mediates TRL clearance. Additionally, hepatocyte-specific inactivation of the heparan sulfate biosynthetic enzymes, GlcNAc N-deacetylase/N-sulfotransferase-1 (Ndst1) and uronyl 2-O-sulftotransferase (Hs2st) using the Cre-loxP system demonstrated the importance of the heparan sulfate chains of Sdc1. Mutant mice bearing defects in heparan sulfate biosynthesis and Sdc1 provide a model for defining genes relevant to hypertriglyceridemia in humans. To better understand how Sdc1 and heparan sulfate structure relate to lipoprotein clearance in the liver, we have the following specific aims:
Aim 1. Determine the structural features of Syndecan-1 that facilitate its action as a lipoprotein receptor in vivo.
Aim 2. Explore the structural features of heparan sulfate required for lipoprotein clearance in vivo.
Aim 3. Characterize the impact of mutations on Syndecan-1 structure and lipoprotein binding in vitro.
Aim 4. Investigate the relative contribution of Syndecan-1 to hepatic clearance of triglyceride-rich lipoproteins in human and mouse hepatocytes. Our genetic analysis of HSPGs in the mouse support the idea that changes in liver heparan sulfate could be an underlying cause of human dyslipidemias. Thus, determining the relevant genes involved in HSPG synthesis in the liver and their functional role in remnant clearance provides a series of candidate genes for eventual allelic analysis in patients with hypertriglyceridemia.
. Hypertriglyceridemia results from the accumulation of triglyceride in the circulation and can occur as a result of genetic deficiencies or as a consequence of chronic alcohol consumption, uncontrolled diabetes, and various drug treatments. Because patients with hypertriglyceridemia have increased risk for atherosclerosis and coronary artery disease, considerable interest exists in understanding its cause and therapy. This grant focuses on understanding how receptors in the liver clear triglycerides from the blood and concentrates in particular of the role of heparan sulfate in this process.
|Thieker, David F; Xu, Yongmei; Chapla, Digantkumar et al. (2018) Downstream Products are Potent Inhibitors of the Heparan Sulfate 2-O-Sulfotransferase. Sci Rep 8:11832|
|Gordts, Philip L S M; Esko, Jeffrey D (2018) The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis. Matrix Biol 71-72:262-282|
|van Wijk, Xander M; Döhrmann, Simon; Hallström, Björn M et al. (2017) Whole-Genome Sequencing of Invasion-Resistant Cells Identifies Laminin ?2 as a Host Factor for Bacterial Invasion. MBio 8:|
|Bergfeld, Anne K; Lawrence, Roger; Diaz, Sandra L et al. (2017) N-glycolyl groups of nonhuman chondroitin sulfates survive in ancient fossils. Proc Natl Acad Sci U S A 114:E8155-E8164|
|Zaiss, Anne K; Foley, Erin M; Lawrence, Roger et al. (2016) Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. J Virol 90:412-20|
|Dwyer, Chrissa A; Esko, Jeffrey D (2016) Glycan susceptibility factors in autism spectrum disorders. Mol Aspects Med 51:104-14|
|Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66|
|Berbée, Jimmy F P; Boon, Mariëtte R; Khedoe, P Padmini S J et al. (2015) Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 6:6356|
|Mooij, Hans L; Bernelot Moens, Sophie J; Gordts, Philip L S M et al. (2015) Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans. J Lipid Res 56:665-73|
|Wen, Jianzhong; Xiao, Junyu; Rahdar, Meghdad et al. (2014) Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis. Proc Natl Acad Sci U S A 111:15723-8|
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