Hepatic remnant lipoprotein clearance by heparan sulfate proteoglycans and low-density lipoprotein receptors depend on dietary conditions in mice

Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2065-74. doi: 10.1161/ATVBAHA.113.301637. Epub 2013 Jul 11.


Objective: Chylomicron and very low-density lipoprotein remnants are cleared from the circulation in the liver by heparan sulfate proteoglycan (HSPG) receptors (syndecan-1), the low-density lipoprotein receptor (LDLR), and LDLR-related protein-1 (LRP1), but the relative contribution of each class of receptors under different dietary conditions remains unclear.

Approach and results: Triglyceride-rich lipoprotein clearance was measured in AlbCre(+)Ndst1(f/f), Ldlr(-/-), and AlbCre(+)Lrp1(f/f) mice and mice containing combinations of these mutations. Triglyceride measurements in single and double mutant mice showed that HSPGs and LDLR dominate clearance under fasting conditions and postprandial conditions, but LRP1 contributes significantly when LDLR is absent. Mice lacking hepatic expression of all 3 receptors (AlbCre(+)Ndst1(f/f) Lrp1(f/f) Ldlr(-/-)) displayed dramatic hyperlipidemia (870 ± 270 mg triglyceride/dL; 1300 ± 350 mg of total cholesterol/dL) and exhibited persistent elevated postprandial triglyceride levels because of reduced hepatic clearance. Analysis of the particles accumulating in mutants showed that HSPGs preferentially clear a subset of small triglyceride-rich lipoproteins (≈ 20-40 nm diameter), whereas LDLR and LRP1 clear larger particles (≈ 40-60 nm diameter). Finally, we show that HSPGs play a major role in clearance of triglyceride-rich lipoproteins in mice fed normal chow or under postprandial conditions but seem to play a less significant role on a high-fat diet.

Conclusions: These data show that HSPGs, LDLR, and LRP1 clear distinct subsets of particles, that HSPGs work independently of LDLR and LRP1, and that HSPGs, LDLR, and LRP1 are the 3 major hepatic triglyceride-rich lipoprotein clearance receptors in mice.

Keywords: cholesterol; heparan sulfate proteoglycans; lipoproteins; low-density lipoprotein receptor; low-density lipoprotein receptor–related protein-1; syndecan-1; triglycerides.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cholesterol, Dietary / administration & dosage
  • Cholesterol, Dietary / metabolism*
  • Chylomicron Remnants / blood
  • Chylomicron Remnants / metabolism*
  • Diet, High-Fat*
  • Dietary Sucrose / administration & dosage
  • Dietary Sucrose / metabolism*
  • Heparan Sulfate Proteoglycans / blood
  • Heparan Sulfate Proteoglycans / metabolism*
  • Hepatocytes / metabolism*
  • Hyperlipidemias / genetics
  • Hyperlipidemias / metabolism
  • Liver / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Particle Size
  • Postprandial Period
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Sulfotransferases / genetics
  • Sulfotransferases / metabolism
  • Time Factors
  • Triglycerides / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • Cholesterol, Dietary
  • Chylomicron Remnants
  • Dietary Sucrose
  • Heparan Sulfate Proteoglycans
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Triglycerides
  • Tumor Suppressor Proteins
  • Sulfotransferases
  • heparitin sulfotransferase