title: Liver sinusoidal endothelial cells depend on mannose receptor-mediated recruitment of lysosomal enzymes for normal degradation capacity.
abstract: Liver sinusoidal endothelial cells (LSECs) are largely responsible for the removal of circulating lysosomal enzymes (LE) via mannose receptor (MR)-mediated endocytosis. We hypothesized that LSECs rely on this uptake to maintain their extraordinarily high degradation capacity for other endocytosed material. Circulatory half-life studies of (125)I-cathepsin-D in MR knockout (MR(-/-)) and wild-type mice, and endocytosis studies in LSEC cultures, showed a total dependence on the MR for effective clearance of cathepsin-D. Radioiodinated formaldehyde-treated serum albumin, a ligand for the LSEC scavenger receptors, was used to study catabolism of endocytosed material in MR(-/-) and wild-type mice. The plasma clearance, liver uptake, and the starting point for release of degradation products to blood, were similar in both experimental groups, indicating normal endocytosis and intracellular transport of scavenger receptor ligands in MR(-/-) mice. However, the rate of formaldehyde-treated serum albumin catabolism in the liver of the MR deficient animals was reduced to approximately 50% of wild-type values. A similar reduction in intracellular degradation was recorded in LSEC cultures from MR(-/-) mice compared to wild-type controls. In accordance with this, MR(-/-) LSECs had markedly and significantly reduced enzyme activities for four out of five LE tested, i.e., cathepsin-D, alpha-mannosidase, beta-hexosaminidase and arylsulfatase, but not acid phosphatase, compared to wild-type controls. Immunoblot analysis showed that the content of pro-cathepsin-D relative to total cathepsin-D in wild-type LSECs was less than one-fifth of that in hepatocytes, indicating lower endogenous LE production in the LSECs.
  
  
  CONCLUSIONS
  We show for the first time that LSEC depend on MR-mediated recruitment of LE from their surroundings for effective catabolism of endocytosed macromolecules.
authors.affiliation: Department of Cell Biology and Histology, University of Tromsø, Tromsø, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Elvevold
authors.forename: Jaione
authors.initials: J
authors.lastname: Simon-Santamaria
authors.forename: Hege
authors.initials: H
authors.lastname: Hasvold
authors.forename: Peter
authors.initials: P
authors.lastname: McCourt
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.forename: Karen Kristine
authors.initials: KK
authors.lastname: Sørensen
mesh_terms: D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology*; D004727:Endothelium / Q000166:cytology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043323:alpha-Mannosidase / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D001192:Arylsulfatases; D043323:alpha-Mannosidase; D001619:beta-N-Acetylhexosaminidases; D002402:Cathepsin D