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.

Public Health Relevance

. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033063-30
Application #
8432828
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Marino, Pamela
Project Start
1983-07-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
30
Fiscal Year
2013
Total Cost
$428,084
Indirect Cost
$150,177
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Inoue, Makoto; Wexselblatt, Ezequiel; Esko, Jeffrey D et al. (2014) Macromolecular uptake of alkyl-chain-modified guanidinoglycoside molecular transporters. Chembiochem 15:676-80
Gasimli, Leyla; Glass, Charles A; Datta, Payel et al. (2014) Bioengineering murine mastocytoma cells to produce anticoagulant heparin. Glycobiology 24:272-80
Sugar, Terrel; Wassenhove-McCarthy, Deborah J; Esko, Jeffrey D et al. (2014) Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo. Kidney Int 85:307-18
Gordts, Philip L S M; Foley, Erin M; Lawrence, Roger et al. (2014) Reducing macrophage proteoglycan sulfation increases atherosclerosis and obesity through enhanced type I interferon signaling. Cell Metab 20:813-26
Gonzales, Jon C; Gordts, Philip L S M; Foley, Erin M et al. (2013) Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J Clin Invest 123:2742-51
Foley, Erin M; Gordts, Philip L S M; Stanford, Kristin I et al. (2013) Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice. Arterioscler Thromb Vasc Biol 33:2065-74
Cantley, Leslie; Saunders, Cheri; Guttenberg, Marta et al. (2013) Loss of ýý-catenin induces multifocal periosteal chondroma-like masses in mice. Am J Pathol 182:917-27
Deng, Yiping; Foley, Erin M; Gonzales, Jon C et al. (2012) Shedding of syndecan-1 from human hepatocytes alters very low density lipoprotein clearance. Hepatology 55:277-86
Le Jan, Sebastien; Hayashi, Makoto; Kasza, Zsolt et al. (2012) Functional overlap between chondroitin and heparan sulfate proteoglycans during VEGF-induced sprouting angiogenesis. Arterioscler Thromb Vasc Biol 32:1255-63

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