INTRAVENOUS HEPARINASE INHIBITS REMNANT LIPOPROTEIN CLEARANCE FROM THE PLASMA AND UPTAKE BY THE LIVER - IN-VIVO ROLE OF HEPARAN-SULFATE PROTEOGLYCANS

Heparan sulfate proteoglycans (HSPG) are involved in the binding and u ptake of apolipoprotein (ape) E-enriched remnant lipoproteins by cultu red cells in vitro. To define the role of hepatic HSPG in remnant lipo protein clearance in vivo, heparinase (30 units) was infused intraveno usly into mice to hydrolyze the liver HSPG and determine the effect of HSPG hydrolysis on remnant clearance by the liver. Liver HSPG were pr elabeled by peritoneal injection of [S-35]Na2SO4. Injection of heparin ase decreased the amount of S-35-labeled liver HSPG by similar to 20-4 0% within 10-15 min. Heparinase infusion significantly inhibited the c learance of chylomicrons, chylomicron remnants, chylomicron remnants apoE, rabbit beta-very low density lipoproteins (beta-VLDL), and beta -VLDL + apoE. Compared with saline injection in control mice, heparina se injection retarded the plasma clearance of the remnants by 1.5- to 2-fold and decreased liver uptake by 1.3- to 1.6-fold. Confocal fluore scence microscopy of thick slices of liver from mice injected with 1,1 '-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine-labeled beta-VLDL + apoE revealed markedly less intense fluorescence from hepatocytes i n heparinase-treated animals compared with those in saline-treated con trol animals. Intravenous heparinase infusion did not inhibit the clea rance of mouse low density lipoproteins (LDL), a ligand for the LDL re ceptor, and did not affect the clearance of alpha(2)-macroglobulin, a ligand for the LDL receptor-related protein. The results suggest an im portant role of the liver HSPG in remnant clearance in vivo.