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 6

Binding, uptake, and degradation of VLDL at 37°C.

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Binding, uptake, and degradation of VLDL at 37°C. (A) Uptake and degrada...
(A) Uptake and degradation of VLDL was measured in wild-type and mutant hepato­cytes after 1 hour of incubation with 20 μg/ml of 125I-VLDL. The bars represent the sum of binding and internalization under these conditions, or the amount of degradation as determined by acid-soluble, non-chloroform–extractable counts in the medium. Binding plus uptake was reduced 2.7-fold in Sdc1–/– cells. Degradation was reduced by nearly 6-fold. (B) Hepatocytes isolated from Sdc1–/– mice treated with AdSdc1 showed enhanced binding and uptake and increased degradation of 125I-VLDL compared with hepatocytes isolated from Sdc1–/– mice treated with AdGFP (P < 0.02). (C) Binding and uptake were also measured in hepatocytes isolated from wild-type, Sdc1–/–, Ldlr–/–, and Ldlr–/–Ndst1f/fAlbCre+ mice. Uptake and binding were reduced 2-fold in the Sdc1–/– and Ldlr–/–Ndst1f/fAlbCre+ hepatocytes compared with wild-type (P < 0.001), while a slight change was observed in Ldlr–/– compared with wild-type (P < 0.05).