Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency

Eskes, Eline C.B.; Lienden, Martijn J.C. van der; Sjouke, Barbara; Vliet, Laura Van de; Brands, M.M.M.G.; Hollak, Carla E. M.; Aerts, Johannes M. F. G.

doi:10.1016/j.ymgme.2023.107631

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…The ileum of Lal KO mice showed a less pronounced Trem2-like phenotype, probably because it had the lowest macrophage accumulation. Of note, the TREM2 signature protein glycoprotein nonmetastatic gene B (GPNMB), a previously described marker for various LSDs, − was strongly upregulated in the jejunum and ileum of LAL KO mice (Figure E,F). In addition, microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB), reported as regulators of Gpnmb expression, were predicted to be significantly activated in these parts of the Lal KO SI (Figure G), confirming the upregulation of the protein itself.…”

Section: Resultsmentioning

confidence: 84%

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Bianco,

Svecla,

Vingiani

et al. 2024

J. Proteome Res.

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The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome. LAL deficiency in patients and mice leads to lipid accumulation, gastrointestinal disturbances, and malabsorption. We previously demonstrated that macrophages massively infiltrated the SI of Laldeficient (KO) mice, especially in the duodenum. Using untargeted proteomics (ProteomeXchange repository, data identifier PXD048378), we revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by a higher expression of GPNMB and concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways, which were downregulated in the jejunum and ileum of Lal KO mice. Our results provide new insights into the process of absorption in control mice and possible novel markers of LAL-D and/or systemic inflammation in LAL-D.

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Section: Resultsmentioning

confidence: 84%

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Bianco,

Svecla,

Vingiani

et al. 2024

J. Proteome Res.

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“…Van Ejik and colleagues were among the first to demonstrate an increase in GPNMB in Gaucher disease spleen and, in particular, in Gaucher cells, the lipid-laden macrophages characteristic of this pathology, accompanied by several hundred-fold increase in circulating sGPNMB concentrations [69]. These discoveries paved the way for many other studies that underscored the importance of GPNMB in Gaucher disease [70][71][72][73] and other LSDs [74][75][76] and, like CHIT1 and CCL18, confirmed its strong association with LSDs and lipid-laden macrophages.…”

Section: Endo/lysosomal Localization Of Glycoprotein Nonmetastatic Me...mentioning

confidence: 98%

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

Bianco,

Kratky

2023

Exp Clin Endocrinol Diabetes

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As a result of an unhealthy diet and limited physical activity, obesity has become a widespread pandemic worldwide and is an important predictor for the development of cardiovascular disease. Obesity is often characterized by a pro-inflammatory environment in white adipose tissue (WAT), mainly due to increased macrophage infiltration. These immune cells boost their lipid concentrations by accumulating the content of dying adipocytes. As the lysosome is highly involved in lipid handling, the progressive lipid accumulation may result in lysosomal stress and a metabolic shift. Recent studies have identified glycoprotein non-metastatic melanoma protein B (GPNMB) as a novel marker of inflammatory diseases. GPNMB is a type I transmembrane protein on the cell surface of various cell types, such as macrophages, dendritic cells, osteoblasts, and microglia, from which it can be proteolytically cleaved into a soluble molecule. It is induced by lysosomal stress via microphthalmia-associated transcription factor and thus has been found to be upregulated in many lysosomal storage disorders. In addition, a clear connection between GPNMB and obesity was recently established. GPNMB was shown to have protective and anti-inflammatory effects in most cases, preventing the progression of obesity-related metabolic disorders. In contrast, soluble GPNMB likely has the opposite effect and promotes lipogenesis in WAT. This review aims to summarize and clarify the role of GPNMB in the progression of obesity and to highlight its potential use as a biomarker for lipid-associated disorders.

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Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8⁺T Cell Activation

Adams,

Sarma,

Hall

et al. 2024

Preprint

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MHC class I molecules play a crucial role in the immune system by presenting peptides derived from intracellular proteins to cytotoxic T lymphocytes (CTLs). This process is essential for immune surveillance and eliminating infected or malignant cells. In some diseases, the immune system fails to recognize and eliminate abnormal cells, leading to disease progression. Under conditions of metabolic dysfunction-associated steatohepatitis (MASH), subsets of CD8+ T cells have been identified as pathogenic, leading to inflammation and fibrosis. Therefore, explicitly targeting factors responsible for T cell activation may be necessary to prevent the onset of MASH and future complications such as cirrhosis or hepatocellular carcinoma. We have identified a specific MHC class I antigen that activates hepatic and splenic CD8+ T cells isolated from MASH mice. To specifically target the antigen, we developed two MHC H2-Kb blocking peptides, MHCP3 and MHCP5, that competitively inhibit the Ncf2 peptide from binding to H2-Kb and reduce activation and proliferation of CD8+ T cells. By inhibiting the recognition of specific antigens, these blocking peptides may prevent the activation of CD8+ T cells and progression of MASH.

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Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency

Cited by 3 publications

References 27 publications

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8⁺T Cell Activation

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Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency

Cited by 3 publications

References 27 publications

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase

Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8+T Cell Activation

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Product

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Development of MHC Class I Blocking Peptides to Target Metabolic Dysfunction-Associated Steatohepatitis CD8⁺T Cell Activation