3- O sulfation of heparin leads to hepatotropism and longer circulatory half-life

Miller, Colton M.; Xu, Yongmei; Kudrna, Katrina M.; Hass, Blake E.; Kellar, Brianna M.; Egger, Andrew W.; Liu, Jian; Harris, Edward N.

doi:10.1016/j.thromres.2018.05.018

Cited by 7 publications

(7 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nuclear magnetic resonance and electrospray ionization mass spectrometry matched published data for 6-mer and 12-mer. Biotinylation of heparin oligosaccharides was performed using previously published methods ( 60 ). The final product was purified by DEAE-HPLC to generate biotinylated 6-mer and 12-mer.…”

Section: Methodsmentioning

confidence: 99%

Comparison of angiopoietin-like protein 3 and 4 reveals structural and mechanistic similarities

Gunn

Gutgsell

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Elevated plasma triglycerides are a risk factor for coronary artery disease, which is the leading cause of death worldwide. Lipoprotein lipase (LPL) reduces triglycerides in the blood by hydrolyzing them from triglyceride-rich lipoproteins to release free fatty acids. LPL activity is regulated in a nutritionally responsive manner by macromolecular inhibitors including angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4). However, the mechanism by which ANGPTL3 inhibits LPL is unclear, in part due to challenges in obtaining pure protein for study. We used a new purification protocol for the N-terminal domain of ANGPTL3, removing a DNA contaminant, and found DNA-free ANGPTL3 showed enhanced inhibition of LPL. Structural analysis showed that ANGPTL3 formed elongated, flexible trimers and hexamers that did not interconvert. ANGPTL4 formed only elongated flexible trimers. We compared the inhibition of ANGPTL3 and ANGPTL4 using human very-low-density lipoproteins as a substrate and found both were noncompetitive inhibitors. The inhibition constants for the trimeric ANGPTL3 (7.5 ± 0.7 nM) and ANGPTL4 (3.6 ± 1.0 nM) were only 2-fold different. Heparin has previously been reported to interfere with ANGPTL3 binding to LPL, so we questioned if the negatively charged heparin was acting in a similar fashion to the DNA contaminant. We found that ANGPTL3 inhibition is abolished by binding to low-molecular-weight heparin, whereas ANGPTL4 inhibition is not. Our data show new similarities and differences in how ANGPTL3 and ANGPTL4 regulate LPL and opens new avenues of investigating the effect of heparin on LPL inhibition by ANGPTL3.

show abstract

Section: Methodsmentioning

confidence: 99%

Comparison of angiopoietin-like protein 3 and 4 reveals structural and mechanistic similarities

Gunn

Gutgsell

et al. 2021

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“… TNFα Cat#4331182 Assay ID- Mm00443258_m1 IL1β Cat#4331182 Assay ID Mm00434228_m1 Experimental models: Cell lines RAW 264.7 cells American Type Culture Collection Cat # TIB-71 EV, Stab1 and Stab2 stably expressing cell lines were created and described previously ( Harris et al., 2004 ; Pempe et al., 2012 ) Experimental models: Organisms/strains Wild-type BALB/c and C57BL/6 male mice 12-16 weeks of age The Jackson Laboratory. 000651, 000664 The F4/80 - CD45 - CD146 + LSEC Using a modified method ( Turman et al., 2021 ) The Stab2 KO mice in C57BL/6 ( Hirose et al., 2012 ) N/A Stab DK mice in C57BL/6 ( Miller et al., 2018 ) ( Miller et al., 2016 ) N/A The TLR4 knockout mice in the C57BL/6 background ( Hoshino et al., 1999 ) Gift The 3 H/ 14 C labeled LPS from Salmonella enterica sv. Typhimurium PR122 (Rc) Kind gift from Prof. Robert Munford (NIAID).…”

Section: Methodsmentioning

confidence: 99%

Stabilin receptors clear LPS and control systemic inflammation

et al. 2021

Self Cite

View full text Add to dashboard Cite

Summary Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.

show abstract

“…The primary function of Stabilin-2 is dependent on the location and expression in the tissues. In the liver, it is highly expressed in liver sinusoidal endothelial cells (LSEC) and is responsible for the systemic clearance of HA [27], natural and infused heparin [25,46], extracellular matrix components such as chondroitin sulfates [32] and collagen pro-peptides [47], advanced glycation end-products [48] and small phosphatidylserine-based particles [49]. Stabilin-2 was first discovered for its HA binding ability.…”

Section: Physiological Functions Of Stabilin-2mentioning

confidence: 99%

Role of the Hyaluronan Receptor, Stabilin-2/HARE, in Health and Disease

Harris

Baker

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Stabilin-2/HARE is the primary clearance receptor for circulating hyaluronan (HA), a polysaccharide found in the extracellular matrix (ECM) of metazoans. HA has many biological functions including joint lubrication, ocular turgor pressure, skin elasticity and hydration, cell motility, and intercellular signaling, among many others. The regulatory system for HA content in the tissues, lymphatics, and circulatory systems is due, in part, to Stabilin-2/HARE. The activity of this receptor was discovered about 40 years ago (early 1980s), cloned in the mid-1990s, and has been characterized since then. Here, we discuss the overall domain organization of this receptor and how it correlates to ligand binding, cellular signaling, and its role in known physiological disorders such as cancer.

show abstract

3- O sulfation of heparin leads to hepatotropism and longer circulatory half-life

Cited by 7 publications

References 47 publications

Comparison of angiopoietin-like protein 3 and 4 reveals structural and mechanistic similarities

Comparison of angiopoietin-like protein 3 and 4 reveals structural and mechanistic similarities

Stabilin receptors clear LPS and control systemic inflammation

Role of the Hyaluronan Receptor, Stabilin-2/HARE, in Health and Disease

Contact Info

Product

Resources

About