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Cited by 226Proteoglycans and glycosaminoglycans researchLipid metabolism and disordersCholesterol and Lipid Metabolism

Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice

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Stanford, Kristin I., Bishop, Joseph R., Foley, Erin M., Gonzales, Jon C., Niesman, Ingrid R., Witztum, Joseph L., Esko, Jeffrey D.·2009·Journal of Clinical Investigation
DOI 10.1172/jci38251PMC PMC2769193
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Abstract

Elevated plasma triglyceride levels represent a risk factor for premature atherosclerosis. In mice, accumulation of triglyceride-rich lipoproteins can occur if sulfation of heparan sulfate in hepatocytes is diminished, as this alters hepatic lipoprotein clearance via heparan sulfate proteoglycans (HSPGs). However, the relevant HSPG has not been determined. In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1-/- mice) accumulated plasma triglycerides. Sdc1-/- mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, facing the space of Disse, where lipoprotein uptake occurs. Abundant syndecan-1 on wild-type murine hepatocytes exhibited saturable binding of VLDL and inhibition by heparin and facilitated degradation of VLDL. Furthermore, adenovirus-encoded syndecan-1 restored binding, uptake, and degradation of VLDL in isolated Sdc1-/- hepatocytes and the lipoprotein clearance defect in Sdc1-/- mice. These findings provide the first in vivo genetic evidence that syndecan-1 is the primary hepatocyte HSPG receptor mediating the clearance of both hepatic and intestinally derived triglyceride-rich lipoproteins.

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  • Syndecan-1 is known to bind and internalize apoE-containing lipoprotein particles, independent of LRP1 in certain cell types.

    “syndecan-1 is known to bind and internalize apoE-containing lipoprotein particles, independent of LRP1 in certain cell types (Stanford et al., 2009; Wilsie et al., 2006).”

    From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Stanford et al., 2009

    The Introduction reports that syndecans internalize lipoprotein preparations enriched in apoE, and the Discussion reports syndecan-1-mediated VLDL binding and uptake. The Discussion suggests syndecan-1 most likely acts independently of LRP receptors under fasting conditions, but says an LRP hand-off mechanism cannot formally be excluded. Thus, this paper does not establish the unqualified LRP1 independence implied by “is known.” No page numbers were supplied for these passages. (LLM, conf=0.86)

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Authors
Stanford, K. I., Bishop, J. R., Foley, E. M., Gonzales, J. C., Niesman, I. R., Witztum, J. L., & Esko, J. D.
Affiliations
University of California San Diego (US)
Corresponding author
Esko, Jeffrey D.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2009-10-01
Volume
119
Issue
11
Pages
3236-45
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci38251
PMC
PMC2769193
OpenAlex
W1999469165
Cited by
226
References
78
Citations by year
2026: 5 · 2025: 9 · 2024: 9 · 2023: 11 · 2022: 9 · 2021: 13 · 2020: 16 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 15 · 2015: 25 · 2014: 16 · 2013: 18 · 2012: 18
FWCI
7.42
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (HL57345)
  • Fondation Leducq
  • National Institutes of Health (HL57345, GM33063, HL088093)
  • University of California, San Diego
  • National Heart, Lung, and Blood Institute (HL 57345, HL-088093, P01HL057345, P01HL088093)
  • National Institute of General Medical Sciences (R01GM033063, R37GM033063, GM-33063)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
syndecan-1, heparan sulfate proteoglycans, triglyceride-rich lipoproteins, VLDL, chylomicrons, hepatocytes, lipoprotein uptake, space of Disse, microvilli, hypertriglyceridemia, atherosclerosis risk, glypican-1, GPC4, syndecan-2, syndecan-4
MeSH terms
Animals, Cells, Cultured, Dietary Fats, Humans, Lipoproteins, Liver, Mice, Inbred C57BL, Microvilli, Triglycerides, Mice, Knockout, Hepatocytes, Mice, Syndecan-1

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