Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism

147

Serum amyloid A isoforms, apoSAA1 and apoSAA2, are apolipoproteins of unknown function that become major components of high density lipoprotein (HDL) during the acute phase of an inflammatory response. ApoSAA is also the precursor of inflammation-associated amyloid, and there is strong evidence that the formation of inflammation-associated and other types of amyloid is promoted by heparan sulfate (HS). Data presented herein demonstrate that both mouse and human apoSAA contain binding sites that are specific for heparin and HS, with no binding for the other major glycosaminoglycans detected. Cyanogen bromide-generated peptides of mouse apoSAA1 and apoSAA2 were screened for heparin binding activity. Two peptides, an apoSAA1-derived 80-mer (residues 24 -103) and a smaller carboxyl-terminal 27-mer peptide of apoSAA2 (residues 77-103), were retained by a heparin column. A synthetic peptide corresponding to the CNBr-generated 27-mer also bound heparin, and by substituting or deleting one or more of its six basic residues (

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

The Heparin/Heparan Sulfate-binding Site on Apo-serum Amyloid A

Ancsin

Kisilevsky

1999

147

“…In addition, direct internalization of lipoproteins bound to the cell surface via heparan sulfate proteoglycans, particularly synde- can and perlecan, may occur without the participation of an LDL receptor family member (35,36). To test the role of proteoglycan in apoE-dependent LDL CE selective uptake in Y1/ E/tet/2/3 cells, we used two approaches to inhibit proteoglycan formation.…”

Section: Detection Of Sr-bi Expression In Y1/e/tet/2/3 and Y1-bs1mentioning

confidence: 99%

The Apolipoprotein E-dependent Low Density Lipoprotein Cholesteryl Ester Selective Uptake Pathway in Murine Adrenocortical Cells Involves Chondroitin Sulfate Proteoglycans and an α2-Macroglobulin Receptor

Swarnakar

Beers

Strickland

et al. 2001

Cells acquire lipoprotein cholesterol by receptor-mediated endocytosis and selective uptake pathways. In the latter case, lipoprotein cholesteryl ester (CE) is transferred to the plasma membrane without endocytosis and degradation of the lipoprotein particle. Previous studies with Y1/E/tet/2/3 murine adrenocortical cells that were engineered to express apolipoprotein (apo) E demonstrated that apoE expression enhances low density lipoprotein (LDL) CE uptake by both selective and endocytic pathways. The present experiments test the hypothesis that apoE-dependent LDL CE selective uptake is mediated by scavenger receptor, class B, type I (SR-BI). Surprisingly, SR-BI expression was not detected in the Y1/E/tet/2/3 clone of Y1 adrenocortical cells, indicating the presence of a distinct apoE-dependent pathway for LDL CE selective uptake. ApoE-dependent LDL CE selective uptake in Y1/E/tet/2/3 cells was inhibited by receptor-associated protein and by activated ␣ 2 -macroglobulin (␣ 2 M), suggesting the participation of the LDL receptor-related protein/␣ 2 M receptor. Reagents that inhibited proteoglycan synthesis or removed cell surface chondroitin sulfate proteoglycan completely blocked apoE-dependent LDL CE selective uptake. None of these reagents inhibited SR-BI-mediated LDL CE selective uptake in the Y1-BS1 clone of Y1 cells in which LDL CE selective uptake is mediated by SR-BI. We conclude that LDL CE selective uptake in adrenocortical cells occurs via SR-BI-independent and SR-BI-dependent pathways. The SR-BI-independent pathway is an apoE-dependent process that involves both chondroitin sulfate proteoglycans and an ␣ 2 M receptor.

“…Support for this proposal comes from the following observations: (i) apoE-or LPL-enhanced internalization of remnant-like lipoproteins is abolished by either enzymatic or genetic removal of HSPGs from the cell surface (24,25); and (ii) in vivo injection of heparinase into the portal vein of mice reduces hepatic clearance of 125 I-labeled ␤-very low density lipoproteins enriched in apoE (25). A role for the independent transport of lipoprotein remnants or LDL into hepatocytes by SDC1, in the absence of other receptors, has also been described (28,29). Importantly, Fuki et al (30,31) showed that transfection of Chinese hamster ovary cells with an expression vector for SDC1 led to a significant increase in the catabolism of lipoproteins enriched in LPL and that chimeric FcR-SDC1 receptors could internalize IgG in the absence of endogenous IgG receptors.…”

mentioning

confidence: 99%

Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor

Anisfeld

Kast-Woelbern

Meyer

et al. 2003

Syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that participates in the binding and internalization of extracellular ligands, was identified in a screen designed to isolate genes that are regulated by the farnesoid X-receptor (FXR, NR1H4). Treatment of human hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein. Transient transfection assays, using wild-type and mutant SDC1 promoter-luciferase genes, led to the identification of a nuclear hormone receptor-binding hexad arranged as a direct repeat separated by one nucleotide (DR-1) in the proximal promoter that was necessary and sufficient for activation by FXR. The wild-type, but not a mutated DR-1 element, conferred FXR responsiveness to a heterologous thymidine kinase promoter-reporter gene. Four murine FXR isoforms have been identified recently that differ either at their amino terminus and/or by the presence or absence of four amino acids in the hinge region. Interestingly, the activities of the human SDC1 promoter-reporter constructs were highly induced by the two FXR isoforms that do not contain the four-amino acid insert and were unresponsive to the isoforms containing the four amino acids. Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner. Increased expression of SDC1 may account in part for the hypotriglyceridemic effect that can result from the administration of chenodeoxycholic acid to humans.