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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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 5

Syndecan-1 mediates binding of VLDL.

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Syndecan-1 mediates binding of VLDL. (A) Wild-type cells were incubated ...
(A) Wild-type cells were incubated with the indicated concentrations of 125I-VLDL in the absence (filled circles) or presence (open circles) of 10 U heparin for 1 hour at 4°C. The amount of binding observed in the presence of heparin was subtracted from the total to obtain specific binding (dashed line, gray circles). (B) Wild-type (filled circles) and Sdc1–/– (filled squares) hepatocytes were incubated with the indicated concentrations of 125I-VLDL for 1 hour at 4°C. A parallel set of cells was incubated under identical conditions with 250 μg/ml of non-radioactive VLDL. Addition of non-radioactive VLDL decreased binding in wild-type hepatocytes (open circles) to nearly the level measured in Sdc1–/– cells (open squares). (C) Deletion of syndecan-1 reduced maximal binding. The counts bound in the presence of excess non-radioactive VLDL in B were subtracted from the raw data, and the net counts were converted to μg VLDL protein bound/mg of cell protein, based on radiospecific activity of the particles (140 cpm/ng). Each data point represents the average of triplicate analyses, which varied by less than the height of the symbol.