Plasma proteome profiling discovers novel proteins associated with non‐alcoholic fatty liver disease

Niu, Lili; Geyer, Philipp; Albrechtsen, Nicolai J. Wewer; Gluud, Lise Lotte; Santos, Alberto; Doll, Sophia; Treit, Peter V.; Holst, Jens J.; Knop, Filip K.; Vilsbøll, Tina; Junker, Anders E; Sachs, Stephan; Stemmer, Kerstin; Müller, Timo; Tschöp, Matthias H.; Hofmann, Susanna M.

doi:10.15252/msb.20188793

Cited by 187 publications

(190 citation statements)

References 82 publications

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“…More than half of all clinical decisions are currently based on blood biomarker analysis 31 . To extend our analysis to the plasma proteome we made use of a recently established high throughput plasma proteomics workflow [31][32][33] (Fig. 6a), and generated plasma proteomes from two independent cohorts of ILD patients (Munich, n=30 and Hannover, n=81; healthy age matched controls, n=30; see Table S10 for clinical characteristics and Table S11 for plasma protein quantifications).…”

Section: Biomarkers Of Lung Health In Plasma Proteomesmentioning

confidence: 99%

Integrated single cell analysis of human lung fibrosis resolves cellular origins of predictive protein signatures in body fluids

Mayr

Simon

Leuschner

et al. 2020

Preprint

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Single cell genomics enables characterization of disease specific cell states, while improvements in mass spectrometry workflows bring the clinical use of body fluid proteomics within reach. The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we leverage single cell RNA-seq and proteomic analysis of large pulmonary fibrosis patient cohorts to identify disease specific changes on the cellular level and their corresponding reflection in body fluid proteomes. We discovered and validated transcriptional changes in 45 cell types across three patient cohorts that translated into distinct changes in the bronchoalveolar lavage fluid and plasma proteome. These protein signatures correlated with diagnosis, lung function, smoking and injury status. Specifically, the altered expression of a novel marker of lung health, CRTAC1, in alveolar epithelium is robustly reflected in patient plasma. Our findings have direct implications for future non-invasive prediction and monitoring of pathological cell state changes in patient organs.

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Section: Biomarkers Of Lung Health In Plasma Proteomesmentioning

confidence: 99%

Integrated single cell analysis of human lung fibrosis resolves cellular origins of predictive protein signatures in body fluids

Mayr

Simon

Leuschner

et al. 2020

Preprint

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“…disease 34 , and a specific glycoform was described as short term predictor of hepatocellular carcinoma in untreated chronic hepatitis B patients 19 . Serum circulating microparticles from systemic lupus erythematosus and venous thromboembolism patients had increases of 90 K 18 .…”

Section: Discussionmentioning

confidence: 99%

Investigating LGALS3BP/90 K glycoprotein in the cerebrospinal fluid of patients with neurological diseases

Costa

Pronto-Laborinho

Pinto

et al. 2020

Sci Rep

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Galectin-3 binding protein (LGALS3BP or 90 K) is a secreted glycoprotein found in human body fluids. Deregulated levels were observed in cancer and infection and its study in neurological diseases is more recent. Here, we have investigated 90 K from human cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS, n = 35) and other neurological diseases (n = 23). CSF was fractionated by ultrafiltration/size-exclusion chromatography (SEC) and eluted fractions were analysed by complementary techniques including immunoblotting, electron microscopy and nano-liquid chromatography-tandem mass spectrometry. A fraction of 90 K appeared as nanoparticles of irregular shape with heterogeneous dimensions of 15-60 nm that co-eluted with extracellular vesicles in SEC. Median levels of 90 K quantified by ELISA were not different between ALS patients (215.8 ng/ml) and controls (213.3 ng/ml) in contrast with the benchmark biomarker for ALS phosphoneurofilament heavy chain (1750 and 345 pg/ml, respectively). A multiregression model supported age is the only independent predictor of 90 K level in both groups (p < 0.05). Significant correlation was found between 90 K levels and age for the ALS group (r = 0.366, p = 0.031) and for all subjects (r = 0.392, p = 0.003). In conclusion, this study unveils the presence of 90 K-containing nanoparticles in human CSF and opens novel perspectives to further investigate 90 K as potential aging marker. Galectin-3-binding protein (LGALS3BP, also known as Mac-2BP or tumor-associated antigen 90 K) is a secretory protein with 567 amino acid residues 1. It is heavily N-glycosylated with seven glycosylation sites 2. In early studies 90 K was purified from supernatants of tumor cells where it appeared as large molecular mass complexes 3. Purified full-length recombinant glycoprotein from human embryonic kidney cells was found to self-associate into non-covalent oligomers of 1000-1500 kDa that appeared as ring-like structures and other shapes by electron microscopy. Recombinant 90 K also associated with collagens IV, V and VI, fibronectin and nidogen, it mediated cell adhesion and it was present in the extracellular matrix of mouse tissues 4. 90 K was visualized by electron microscopy in nanoparticles of irregular shape found in extracellular vesicle (EV) fractions from tumor cells in culture 5. More recently, asymmetric flow field-flow fractionation revealed novel nanoparticles from supernatants of tumor cells in culture termed exomeres, which contained 90 K 6. Cells from the human body as well as cells in culture release EV to the surroundings. EV include two major groups, exosomes of endosomal origin and microvesicles that derive from the plasma membrane of cells. EV can be found in body fluids, such as blood 7 or CSF 8-11 and constitute promising tools in disease diagnosis 12. In view of EV heterogeneity several isolation techniques have been used including ultracentrifugation and size-exclusion chromatography (SEC) 12 .

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“…This trend reflects to some degree the reported trends in the serum concentration of the proteins in liver cirrhosis. We observe lower intensities in the non-fucosylated glycopeptides of proteins (hemopexin, clusterin, ITIH4, fibrinogen) reported to decrease in cirrhosis while the nonfucosylated glycopeptide of alpha-2 macroglobulin has higher intensity in cirrhosis in line with its increased serum concentration [40][41][42] . However, additional factors affect the abundance of the non-fucosylated glycopeptides because some glycoforms of the same peptide show inconsistent trends.…”

Section: Trends In the Abundance Of Fucosylated And Non-fucosylated Gmentioning

confidence: 98%

Analysis of site and structure specific core fucosylation in liver disease progression using exoglycosidase-assisted data-independent LC-MS/MS

Šanda

Ahn

Kozlík³

et al. 2020

Preprint

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Carbohydrates form one of the major groups of biological macromolecules in living organisms. Many biological processes including protein folding, stability, immune response, and receptor activation are regulated by glycosylation. Fucosylation of proteins regulates such processes and is associated with various diseases including autoimmunity and cancer. Mass spectrometry efficiently identifies structures of fucosylated glycans or sites of core fucosylated N-glycopeptides but quantification of the glycopeptides remains less explored. We performed experiments that facilitate quantitative analysis of the core fucosylation of proteins with partial structural resolution of the glycans and we present results of the mass spectrometric SWATH-type DIA analysis of relative abundances of the core fucosylated glycoforms of 45 glycopeptides derived from 18 serum proteins in liver disease of different etiologies. Our results show that a combination of soft fragmentation with exoglycosidases is efficient at the assignment and quantification of the core fucosylated N-glycoforms at specific sites of protein attachment. In addition, our results show that disease-associated changes in core fucosylation are peptide-dependent and further differ by branching of the core fucosylated glycans. Further studies are needed to verify whether tri- and tetra-antennary core fucosylated glycopeptides could be used as markers of liver disease progression.

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Plasma proteome profiling discovers novel proteins associated with non‐alcoholic fatty liver disease

Cited by 187 publications

References 82 publications

Integrated single cell analysis of human lung fibrosis resolves cellular origins of predictive protein signatures in body fluids

Integrated single cell analysis of human lung fibrosis resolves cellular origins of predictive protein signatures in body fluids

Investigating LGALS3BP/90 K glycoprotein in the cerebrospinal fluid of patients with neurological diseases

Analysis of site and structure specific core fucosylation in liver disease progression using exoglycosidase-assisted data-independent LC-MS/MS

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