scholarly journals Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin

2021 ◽  
Author(s):  
Delia Susan-Resiga ◽  
Emmanuelle Girard ◽  
Rachid Essalmani ◽  
Anna Roubtsova ◽  
Jadwiga Marcinkiewicz ◽  
...  
Keyword(s):  
Cell Surface ◽  
Hdl Cholesterol ◽  
Asialoglycoprotein Receptor ◽  
Carbohydrate Binding ◽  
Loss Of Function ◽  
Novel Approach ◽  
Terminal Galactose ◽  
Ldl Uptake ◽  
Artery Disease

ABSTRACTThe hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote-carriers of ASGR1-deletions exhibited ~34% lower risk of coronary artery disease and ~10-14% non-HDL-cholesterol reduction. Since PCSK9 is a major degrader of LDLR, we examined the regulation of LDLR and/or PCSK9 by ASGR1. We investigated the role of endogenous/overexpressed ASGR1 on LDLR degradation and functionality in naïve HepG2 and HepG2-PCSK9-knockout cells by Western-blot and immunofluorescence.ASGR1, like PCSK9, targets LDLR and both interact with/enhance the degradation of the receptor independently. The lack of cooperativity between PCSK9 and ASGR1 on LDLR expression was confirmed in livers of wild-type (WT) versus Pcsk9-/- mice. ASGR1-knockdown in naïve HepG2 cells significantly increased total (~1.2-fold) and cell-surface (~4-fold) LDLR protein. In HepG2-PCSK9-knockout cells ASGR1-silencing led to ~2-fold higher levels of LDLR protein and DiI-LDL uptake associated with ~4-fold increased cell-surface LDLR. Overexpression of WT-ASGR1 reduced primarily the immature non-O-glycosylated LDLR (~110 kDa), whereas the triple Gln240/Trp244/Glu253 Ala-mutant (loss of carbohydrate-binding) reduced the mature form of the LDLR (~150 kDa), suggesting that ASGR1 binds the LDLR in sugar-dependent and -independent fashion. Furin sheds ASGR1 at RKMK103↓ into a secreted form, likely resulting in a loss-of-function on LDLR. LDLR is the first example of a liver-receptor ligand of ASGR1. Additionally, we demonstrate that lack of ASGR1 enhances LDLR levels and DiI-LDL incorporation, independently of PCSK9. Overall, silencing of ASGR1 and PCSK9 may lead to higher LDL-uptake by hepatocytes, thereby providing a novel approach to further reduce LDL-cholesterol.

scholarly journals MBRS-17. EXAMINING THE ROLE OF LHX9 IN GROUP 3 MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii401-iii401
Author(s):  
Sarah Injac ◽  
L Frank Huang ◽  
Stephen Mack ◽  
Frank Braun ◽  
Yuchen Du ◽  
...  
Keyword(s):  
Drug Repositioning ◽  
Single Agent ◽  
Xenograft Model ◽  
Cell Killing ◽  
Rna Seq ◽  
Loss Of Function ◽  
Novel Treatments ◽  
Novel Approach ◽  
Group 3

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition raising the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.

Desialylated Platelets Are Cleared From the Circulation by the Hepatic Asialoglycoprotein Receptor,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3257-3257
Author(s):  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Karin M. Hoffmeister
Keyword(s):  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Asialoglycoprotein Receptor ◽  
Regulatory Mechanisms ◽  
Wild Type ◽  
Cell Counts ◽  
Blood Cell Counts ◽  
Terminal Galactose

Abstract Abstract 3257 The regulatory mechanisms of platelet homeostasis remain elusive. We investigated here the role of hepatic asialoglycoprotein receptor (a.k.a. Ashwell-Morell receptor) in platelet clearance. Mice lacking the hepatic asialoglycoprotein receptor Asgpr2 subunit had increased platelet survivals (T1/2 = 49.5±2h) when compared to wild type (WT, T1/2 = 31±4h) mice. Consequently, Asgpr2−/− mice had platelet counts increased by ∼20%, compared to WT, with increased terminal galactose exposure, as demonstrated using the galactose specific lectin RCA1. Bone marrow and spleen megakaryocyte numbers were reduced by ∼15% and ∼20% in Asgpr2−/− mice, compared to WT mice. Sialidase (NA, Clostidium perfringens, 50mU/mice) maximally desialylated circulating platelets when injected intravenously, as evidenced by increased RCA1 binding. Sialidase injection resulted in a ∼60% depletion of circulating platelets after 24h in Asgpr2−/− mice, compared to >90% in WT mice, indicating that desialylated platelets were partially removed by Asgpr1/2. In contrast to platelets, red blood cell counts were unaffected by sialidase treatment. Sialidase injection for 72h resulted in a 2.3-fold and 1.2-fold increase in megakaryocyte numbers in the spleen and bone marrow of WT mice, respectively, but not in Asgpr2−/− mice. In contrast to sialidase treatment, injections of rabbit anti-mouse platelet serum (RAMPS) depleted >95% of circulating platelets and increased by 70% bone marrow, but not spleen MK numbers in both WT and Asgpr2−/− mice. The data shows that removal of desialylated, i.e, senescent, platelets by the hepatic Ashwell-Morell receptor differs to that of antibody-mediated platelet clearance. Disclosures: No relevant conflicts of interest to declare.

Abstract P306: Increase of the Inflammatory Burden at a Young Age in Patients with Coronary Artery Disease

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Enkhmaa Byambaa ◽  
Anuurad Erdembileg ◽  
Wei Zhang ◽  
Kyoungmi Kim ◽  
Lars Berglund
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
African Americans ◽  
Inflammatory Markers ◽  
Hdl Cholesterol ◽  
Amyloid A ◽  
Rate Of Increase ◽  
Artery Disease ◽  
Inflammatory Burden

Introduction: Age and inflammation both are considered risk factors for coronary artery disease (CAD) and the levels of inflammatory markers increase with aging. However, the role of age-induced inflammatory burden in CAD development is not fully understood. We investigated the trajectories of inflammatory markers with increasing age in subjects with or without CAD. Hypothesis: We hypothesized that the rate of increase in inflammatory markers as a function of age would depend on the presence of CAD and differ between subjects with and without CAD. Methods: Systemic inflammatory burden was assessed by levels of C-reactive protein (CRP), serum amyloid A (SAA) and fibrinogen in Caucasians (n=184) and African-Americans (n=154) (age range: 20-60 years). The presence of CAD was defined as the presence of ≥50% stenosis in any one of 15 coronary artery segments. Results: The prevalence of CAD was 46% (85 of 184) and 38% (58 of 154) in Caucasians and African-Americans, respectively. In both ethnic groups, subjects with CAD were older and had an atherogenic lipid profile compared to subjects without CAD. For both subjects with and without CAD, HDL cholesterol level was significantly higher and triglyceride level was significantly lower in African-Americans compared to Caucasians. The pattern of inflammatory burden over age differed across CAD status and ethnicity. Among Caucasians, the trend patterns of CRP (p<0.05), SAA (p<0.01) and fibrinogen (p<0.001) over age differed significantly between subjects with and without CAD. Levels of all three markers were elevated already at young ages and remained relatively constant over age in Caucasians with CAD. In contrast, in Caucasians without CAD, the levels of these markers were lower at young ages with a gradual increase over age. The findings for African-Americans differed from that of Caucasians. The levels of inflammatory markers increased with age with no significant differences in trends between subjects with and without CAD. In multivariate analyses adjusting for covariates, the trend pattern of fibrinogen over age differed significantly between Caucasians with and without CAD. Conclusions: There was a diverging pattern in age-induced inflammatory burden associated with CAD, with an early start and faster rate of increase in Caucasian patients with CAD. The findings suggest an accelerated inflammation over age in individuals with CAD with a possible modulatory role of ethnicity/race.

scholarly journals Function of AtPGAP1 in GPI anchor lipid remodeling and transport to the cell surface of GPI-anchored proteins

2021 ◽  
Author(s):  
César Bernat-Silvestre ◽  
Judit Sanchez-Simarro ◽  
Yingxuan Ma ◽  
Kim Johnson ◽  
Fernando Aniento ◽  
...  
Keyword(s):  
Cell Surface ◽  
Acyl Chain ◽  
Growth Stress ◽  
Loss Of Function ◽  
Gpi Anchor ◽  
C Terminus ◽  
Gpi Transamidase ◽  
Er Export ◽  
Inositol Ring

ABSTRACTGPI-anchored proteins (GPI-APs) play an important role in a variety of plant biological processes including growth, stress response, morphogenesis, signalling and cell wall biosynthesis. The GPI-anchor contains a lipid-linked glycan backbone that is synthesized in the endoplasmic reticulum (ER) where it is subsequently transferred to the C-terminus of proteins containing a GPI signal peptide by a GPI transamidase. Once the GPI anchor is attached to the protein, the glycan and lipid moieties are remodelled. In mammals and yeast, this remodelling is required for GPI-APs to be included in Coat Protein II (COPII) coated vesicles for their ER export and subsequent transport to the cell surface. The first reaction of lipid remodelling is the removal of the acyl chain from the inositol group by Bst1p (yeast) and PGAP1 (mammals). In this work, we have used a loss-of-function approach to study the role of PGAP1/Bst1 like genes in plants. We have found that Arabidopsis PGAP1 localizes to the ER and probably functions as the GPI inositol-deacylase which cleaves the acyl chain from the inositol ring of the GPI anchor. In addition, we show that PGAP1 function is required for efficient ER export and transport to the cell surface of GPI-APs.One sentence summaryGPI anchor lipid remodeling in GPI-anchored proteins is required for their transport to the cell surface in Arabidopsis.

scholarly journals MiR-21-3p Inhibits Adipose Browning by Targeting FGFR1 and Aggravates Atrial Fibrosis in Diabetes

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Jian-an Pan ◽  
Hao Lin ◽  
Jian-ying Yu ◽  
Hui-li Zhang ◽  
Jun-feng Zhang ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Growth Factor Receptor ◽  
Loss Of Function ◽  
Wild Type ◽  
Atrial Fibrosis ◽  
Novel Approach ◽  
Diabetic Model ◽  
Coculture Model ◽  
Direct Target

A relationship between excess epicardial adipose tissue (EAT) and the risk of atrial fibrillation (AF) has been reported. Browning of EAT may be a novel approach for the prevention or treatment of AF by attenuating atrial fibrosis. Previous studies have identified microRNA-21 (miR-21) as a regulatory factor in atrial fibrosis. The present study examined the role of different subtypes of miR-21 in adipose browning and atrial fibrosis under hyperglycemic conditions. Wild type and miR-21 knockout C57BL/6 mice were used to establish a diabetic model via intraperitoneal injection of streptozotocin. A coculture model of atrial fibroblasts and adipocytes was also established. We identified miR-21-3p as a key regulator that controls adipocyte browning and participates in atrial fibrosis under hyperglycemic conditions. Moreover, fibroblast growth factor receptor (FGFR) 1, a direct target of miR-21-3p, decreased in this setting and controlled adipose browning. Gain and loss-of-function experiments identified a regulatory pathway in adipocytes involving miR-21a-3p, FGFR1, FGF21, and PPARγ that regulated adipocyte browning and participated in hyperglycemia-induced atrial fibrosis. Modulation of this signaling pathway may provide a therapeutic option for the prevention and treatment of atrial fibrosis or AF in DM.

scholarly journals Role of sialic acid for platelet life span: exposure of β-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor–expressing liver macrophages and hepatocytes

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1645-1654 ◽  
Author(s):  
Anne Louise Sørensen ◽  
Viktoria Rumjantseva ◽  
Sara Nayeb-Hashemi ◽  
Henrik Clausen ◽  
John H. Hartwig ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Blood Cells ◽  
Asialoglycoprotein Receptor ◽  
Platelet Surface ◽  
Terminal Galactose ◽  
Report Data ◽  
Rapid Clearance ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractAlthough surface sialic acid is considered a key determinant for the survival of circulating blood cells and glycoproteins, its role in platelet circulation lifetime is not fully clarified. We show that thrombocytopenia in mice deficient in the St3gal4 sialyltransferase gene (St3Gal-IV−/− mice) is caused by the recognition of terminal galactose residues exposed on the platelet surface in the absence of sialylation. This results in accelerated platelet clearance by asialoglycoprotein receptor-expressing scavenger cells, a mechanism that was recently shown to induce thrombocytopenia during Streptococcus pneumoniae sepsis. We now identify platelet GPIbα as a major counterreceptor on ST3Gal-IV−/− platelets for asialoglycoprotein receptors. Moreover, we report data that establish the importance of sialylation of the von Willebrand factor in its function.

scholarly journals Loss-of-function mutation in Pcsk1 increases serum APOA1 level and LCAT activity in mice

2022 ◽  
Vol 38 (1) ◽  
Author(s):  
Aleksandra Aljakna Khan ◽  
Nakyung Kim ◽  
Ron Korstanje ◽  
Seungbum Choi
Keyword(s):  
Cholesterol Metabolism ◽  
Wide Spectrum ◽  
Hdl Cholesterol ◽  
Apolipoprotein A1 ◽  
Cholesterol Concentration ◽  
Lcat Activity ◽  
Loss Of Function ◽  
Nucleotide Mutation ◽  
Hdl Metabolism

Abstract Background The convertase subtilisin/kexin family 1 gene (PCSK1) has been associated in various human genetics studies with a wide spectrum of metabolic phenotypes, including early-onset obesity, hyperphagia, diabetes insipidus, and others. Despite the evident influence of PCSK1 on obesity and the known functions of other PCSKs in lipid metabolism, the role of PCSK1 specifically in lipid and cholesterol metabolism remains unclear. This study evaluated the effect of loss of PCSK1 function on high-density lipoprotein (HDL) metabolism in mice. Results HDL cholesterol, apolipoprotein A1 (APOA1) levels in serum and liver, and the activities of two enzymes (lecithin-cholesterol acyltransferase, LCAT and phospholipid transfer protein, PLTP) were evaluated in 8-week-old mice with a non-synonymous single nucleotide mutation leading to an amino acid substitution in PCSK1, which results in a loss of protein’s function. Mutant mice had similar serum HDL cholesterol concentration but increased levels of serum total and mature APOA1, and LCAT activity in comparison to controls. Conclusions This study presents the first evaluation of the role of PCSK1 in HDL metabolism using a loss-of-function mutant mouse model. Further investigations will be needed to determine the underlying molecular mechanism.

The Role of Non-HDL Cholesterol in Risk Stratification for Coronary Artery Disease

2011 ◽  
Vol 14 (2) ◽  
pp. 130-134 ◽  
Author(s):  
Jamal S. Rana ◽  
S. Matthijs Boekholdt ◽  
John J. P. Kastelein ◽  
Prediman K. Shah
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Stratification ◽  
Hdl Cholesterol ◽  
Artery Disease

Abstract 12976: Higher Triglyceride Level is Associated With Higher Frequency of Macrophage Accumulation in Coronary Plaques

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kiyoshi Asakura ◽  
Yoshiyasu Minami ◽  
Masahiro Katamine ◽  
Ayami Kato ◽  
Aritomo Katsura ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Hdl Cholesterol ◽  
Coronary Plaque ◽  
Culprit Lesion ◽  
Oct Imaging ◽  
Artery Disease ◽  
The Impact ◽  
High Triglyceride ◽  
Macrophage Accumulation

Introduction: The impact of high triglyceride (TG) level on the characteristics of coronary plaque remains to be elucidated. Hypothesis: Higher TG level is associated with higher prevalence of vulnerable coronary plaque in patients with coronary artery disease (CAD). Methods: A total of 865 consecutive patients who underwent optical coherence tomography (OCT) imaging of the culprit lesion were included. Patients were classified into either the higher TG group (non-fasting TG ≥ 200 mg/dL, n=150) or the lower TG group (non-fasting TG < 200 mg/dL, n=715). The morphologies of culprit plaque assessed by OCT were compared between the two groups. Results: The median (interquartile range) of TG in the 2 groups was 265.5 (221.5 – 314.8) mg/dL and 115.0 (84.0 – 152.0) mg/dL, respectively. The frequency of macrophage accumulation was significantly higher in the higher TG group than the lower TG group (41 vs. 33%, p=0.043) (Panel A), whereas the prevalence of other plaque components including thin-cap fibroatheroma (22 vs. 19%, p=0.386), microchannel (24 vs. 25%, p=0.907) and cholesterol crystal (23 vs. 23%, p=0.862) was comparable between the two groups. The incremental frequency of macrophage accumulation according to TG levels was observed (p=0.015, Panel B). Although the frequency of macrophage accumulation was comparable between the 2 groups among patients with a higher HDL cholesterol (HDL-C) level (>35 mg/dL), macrophage accumulation was significantly more frequent in the higher TG group than in the lower TG group (71 vs. 41%, p=0.032) among patients with a lower HDL-C level (≤35 mg/dL). Conclusions: Higher TG level was associated with higher frequency of macrophage accumulation in culprit plaques in patients with CAD. The present results may partly explain the role of TG on the development of culprit plaque in coronary artery.

scholarly journals A robust method to estimate regional polygenic correlation identifies heterogeneity in the shared heritability between complex traits

2017 ◽  
Author(s):  
Guillaume Paré ◽  
Shihong Mao ◽  
Wei Q. Deng
Keyword(s):  
Complex Traits ◽  
Potential Role ◽  
Hdl Cholesterol ◽  
Polygenic Effect ◽  
Genome Wide ◽  
Novel Method ◽  
Artery Disease ◽  
Genomic Regions ◽  
Epidemiological Association

AbstractBackgroundComplex traits can share a substantial proportion of their polygenic heritability. However, genome-wide polygenic correlations between pairs of traits can mask heterogeneity in their shared polygenic effects across loci. We propose a novel method (WML-RPC) to evaluate polygenic correlation between two complex traits in small genomic regions using summary association statistics. Our method tests for evidence that the polygenic effect at a given region affects two traits concurrently.ResultsWe show through simulations that our method is well calibrated, powerful and more robust to misspecification of linkage disequilibrium than other methods under a polygenic model. As small genomic regions are more likely to harbour specific genetic effects, our method is ideal to identify heterogeneity in shared polygenic correlation across regions. We illustrate the usefulness of our method by addressing two questions related to cardio-metabolic traits. First, we explored how regional polygenic correlation can inform on the strong epidemiological association between HDL cholesterol and coronary artery disease (CAD), suggesting a key role for triglycerides metabolism. Second, we investigated the potential role of PPARγ activators in the prevention of CAD.ConclusionsOur results provide a compelling argument that shared heritability between complex traits is highly heterogeneous across loci.

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