Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice
Kristin I. Stanford, … , Joseph L. Witztum, Jeffrey D. Esko
Kristin I. Stanford, … , Joseph L. Witztum, Jeffrey D. Esko
Published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3236-3245. https://doi.org/10.1172/JCI38251.
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Research Article Cardiology

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

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.

Authors

Kristin I. Stanford, Joseph R. Bishop, Erin M. Foley, Jon C. Gonzales, Ingrid R. Niesman, Joseph L. Witztum, Jeffrey D. Esko

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Figure 3

Sdc1–/– mice exhibit delayed plasma clearance of triglycerides and postprandial lipoproteins.

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Sdc1–/– mice exhibit delayed plasma clearance of triglycerides and post...
(A) Clearance of human VLDL apoB-100 was measured by ELISA using human apoB-100–specific mAb MB47. Representative data from 3 different experiments is shown and plotted on a semi-log scale. Wild-type mice, t1/2 = 46 ± 7 minutes (n = 6 mice); Sdc1–/– mice, t1/2 = 92 ± 18 min (n = 6 mice). The difference in t1/2 between the genotypes was significant (P = 0.0009). (B) Retinol ester clearance was measured in wild-type (filled circles, n = 3), and Sdc1–/– (open circles, n = 3) mice. Animals were fasted for 4 hours and given 200 μl of corn oil containing [3H]retinol by gavage. Blood samples were taken and radioactivity remaining in 10 μl of serum was determined by scintillation counting. The values are expressed as mean ± SD. The areas under the curve were 4,100 ± 1,200 for the wild-type and 8,400 ± 30 for Sdc1–/– mice. Clearance was significantly delayed in Sdc1–/– mice compared with wild-type (P = 0.0034). Right: Triglyceride values were measured 4 hours after injection. (C) Sdc1–/– mice were injected with AdSdc1 (n = 6 mice) or AdGFP (n = 6 mice). Plasma retinol ester levels were measured as described above and compared with wild-type mice (filled circles). The areas under the curve were 3,700 ± 1,100 for wild-type, 7,400 ± 2,600 for AdGFP Sdc1–/–, and 3,200 ± 900 for AdSdc1 Sdc1–/–. Animals treated with AdSdc1 demonstrated clearance similar to that wild-type animals (gray circles, P = 0.1272) and significantly faster clearance than Sdc1–/– mice treated with AdGFP (P = 0.0037).