Discovery of the Liver Hyaluronan Receptor for Endocytosis (HARE) and Its Progressive Emergence as the Multi-Ligand Scavenger Receptor Stabilin-2

Weigel, Paul H.

doi:10.3390/biom9090454

Cited by 14 publications

(16 citation statements)

References 57 publications

(144 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stabilin-1 is also known as SR-H1/MS-1/FEEL-1/CLEVER-1. Stabilin-2 is also known as SR-H2/FEEL-2 and HARE, which is a shorter isoform of Stabilin-2 generated by proteolytic cleavage (Goerdt et al, 1991;Weigel, 2019). The main structural difference between Stabilin-1 and Stabilin-2 is the presence of 20 EGF-like domains in stabilin-2 as compared to 21 domains in stabilin-1.…”

Section: Scavenger Receptor H (Sr-h)mentioning

confidence: 99%

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

2020

View full text Add to dashboard Cite

Liver sinusoidal endothelial cells (LSECs) are the most abundant non-parenchymal cells lining the sinusoidal capillaries of the hepatic system. LSECs are characterized with numerous fenestrae and lack basement membrane as well as a diaphragm. These unique morphological characteristics of LSECs makes them the most permeable endothelial cells of the mammalian vasculature and aid in regulating flow of macromolecules and small lipid-based structures between sinusoidal blood and parenchymal cells. LSECs have a very high endocytic capacity aided by scavenger receptors (SR), such as SR-A, SR-B (SR-B1 and CD-36), SR-E (Lox-1 and mannose receptors), and SR-H (Stabilins). Other high-affinity receptors for mediating endocytosis include the FcγRIIb, which assist in the antibody-mediated removal of immune complexes. Complemented with intense lysosomal activity, LSECs play a vital role in the uptake and degradation of many blood borne waste macromolecules and small (<280 nm) colloids. Currently, seven Toll-like receptors have been investigated in LSECs, which are involved in the recognition and clearance of pathogen-associated molecular pattern (PAMPs) as well as damage associated molecular pattern (DAMP). Along with other SRs, LSECs play an essential role in maintaining lipid homeostasis with the lowdensity lipoprotein receptor-related protein-1 (LRP-1), in juxtaposition with hepatocytes. LSECs co-express two surface lectins called L-Specific Intercellular adhesion molecule-3 Grabbing Non-integrin Receptor (L-SIGN) and liver sinusoidal endothelial cell lectin (LSECtin). LSECs also express several adhesion molecules which are involved in the recruitment of leukocytes at the site of inflammation. Here, we review these cell surface receptors as well as other components expressed by LSECs and their functions in the maintenance of liver homeostasis. We further discuss receptor expression and activity and dysregulation associated with the initiation and progression of many liver diseases, such as hepatocellular carcinoma, liver fibrosis, and cirrhosis, alcoholic and non-alcoholic fatty liver diseases and pseudocapillarization with aging.

show abstract

Section: Scavenger Receptor H (Sr-h)mentioning

confidence: 99%

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

2020

View full text Add to dashboard Cite

show abstract

“…Dextran sulfate is an inhibitor of stabilin-2 and related scavenger receptors. Since stabilin-2 mediates cellular uptake of negatively charged macromolecules or nanoparticles by a clathrin-coated pit pathway ( 69 ), it is reasonable to assume that in our experiments not the free fluorescent small molecule was recognized but a protein-associated conjugate thereof. Indeed, cyclosporine analogs are characterized by a very high protein binding of >98% ( 70 ).…”

Section: Discussionmentioning

confidence: 98%

Zebrafish (Danio rerio) larva as an in vivo vertebrate model to study renal function

Bolten

Pratsinis

Alter

et al. 2022

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

There is an increasing interest in using the zebrafish (Danio rerio) larva as a vertebrate screening model to study drug disposition. Since the pronephric kidney of zebrafish larvae shares high similarity with the anatomy of nephrons in higher vertebrates including humans, we explored in the present study whether 3 to 4 days old zebrafish larvae have a fully functional pronephron. Intravenous injection of fluorescent polyethylene glycol and dextran derivatives of different molecular weight revealed a cut-off of 4.4 to 7.6 nm in hydrodynamic diameter for passive glomerular filtration, which is in agreement with corresponding values in rodents and humans. Distal tubular reabsorption of a FITC-folate conjugate, covalently modified with PEG2000, via the folate receptor 1 was shown. Transport experiments of fluorescent substrates were assessed in the presence and absence of specific inhibitors in the blood systems. Thereby, functional expression in the proximal tubule of oat/slc22, mrp1/abcc1, mrp2/abcc2, mrp4/abcc4 and the zebrafish larvaes' p-glycoprotein analog abcb4 was shown. In addition, non-renal clearance of fluorescent substrates and plasmaprotein binding characteristics were assessed in vivo. Results of transporter studies were confirmed by extrapolation to ex vivo experiments in killifish (Fundulus heteroclitus) proximal kidney tubules. We conclude that the zebrafish larva has a fully functional pronephron at 96 hours post fertilization and is therefore an attractive translational vertebrate screening model to bridge the gap between cell culture-based test systems and pharmacokinetic experiments in higher vertebrates.

show abstract

“…Most significantly, the addition of exogenous HA eliminated these intracellular pools in both the absence and presence of LPS stimulation. Whether the accumulation of intracellular HA is due to recycling of newly synthesized HA via phago/endocytosis [ 77 ] involving CD44 [ 78 ] and/or Stabilin 2 [ 79 ] remains to be established. Thus, alternatively, these vesicular structures could be the result of fusion of auto-phagosomes with lysosomes [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Addition of High Molecular Weight Hyaluronic Acid to Fibroblast-Like Stromal Cells Modulates Endogenous Hyaluronic Acid Metabolism and Enhances Proteolytic Processing and Secretion of Versican

Xue

Chen

Shen

et al. 2020

Cells

View full text Add to dashboard Cite

We have examined the effect of exogenous linear chain high molecular weight hyaluronic acid (HMW HA) on endogenously synthesized hyaluronic acid (HA) and associated binding proteins in primary cultures of fibroblast-like stromal cells that were obtained by collagenase digestion of the murine peripatellar fat pad. The cultures were expanded in DMEM that was supplemented with fetal bovine serum and basic fibroblast growth factor (bFGF) then exposed to macrophage-colony-stimulating factor (MCSF) to induce macrophage properties, before activation of inflammatory pathways using E. coli lipopolysaccharide (LPS). Under all culture conditions, a significant amount of endogenously synthesized HA localized in LAMP1-positive lysosomal vesicles. However, this intracellular pool was depleted after the addition of exogenous HMW HA and was accompanied by enhanced proteolytic processing and secretion of de novo synthesized versican, much of which was associated with endosomal compartments. No changes were detected in synthesis, secretion, or proteolytic processing of aggrecan or lubricin (PRG4). The addition of HMW HA also modulated a range of LPS-affected genes in the TLR signaling and phagocytosis pathways, as well as endogenous HA metabolism genes, such as Has1, Hyal1, Hyal2, and Tmem2. However, there was no evidence for association of endogenous or exogenous HMW HA with cell surface CD44, TLR2 or TLR4 protein, suggesting that its physiochemical effects on pericelluar pH and/or ionic strength might be the primary modulators of signal transduction and vesicular trafficking by this cell type. We discuss the implications of these findings in terms of a potential in vivo effect of therapeutically applied HMW HA on the modification of osteoarthritis-related joint pathologies, such as pro-inflammatory and degradative responses of multipotent mesenchymal cells residing in the synovial membrane, the underlying adipose tissue, and the articular cartilage surface.

show abstract

Discovery of the Liver Hyaluronan Receptor for Endocytosis (HARE) and Its Progressive Emergence as the Multi-Ligand Scavenger Receptor Stabilin-2

Cited by 14 publications

References 57 publications

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

Prominent Receptors of Liver Sinusoidal Endothelial Cells in Liver Homeostasis and Disease

Zebrafish (Danio rerio) larva as an in vivo vertebrate model to study renal function

Addition of High Molecular Weight Hyaluronic Acid to Fibroblast-Like Stromal Cells Modulates Endogenous Hyaluronic Acid Metabolism and Enhances Proteolytic Processing and Secretion of Versican

Contact Info

Product

Resources

About