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

Abstract

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.

Key words

adipose tissue macrophages - glycoprotein non-metastatic melanoma protein B - lipid-associated disorders - lysosomal storage disorders - osteoactivin

Publication History

Received: 03 August 2023
Received: 25 September 2023

Accepted: 06 October 2023

Article published online:
13 November 2023

• References

• 1 The Lancet Gastroenterology & Hepatology. Obesity: Another ongoing pandemic. Lancet Gastroenterol Hepatol 2021; 6: 411
• 2 Ortega FB, Lavie CJ, Blair SN. Obesity and cardiovascular disease. Circ Res 2016; 118: 1752-1770
• 3 Safaei M, Sundararajan EA, Driss M. et al. A systematic literature review on obesity: Understanding the causes & consequences of obesity and reviewing various machine learning approaches used to predict obesity. Comput Biol Med 2021; 136: 104754
• 4 Haslam DW, James WPT. Obesity. The Lancet 2005; 366: 1197-1209
• 5 Xu H, Barnes GT, Yang Q. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-1830
• 6 Weisberg SP, McCann D, Desai M. et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
• 7 Oliveros E, Somers VK, Sochor O. et al. The concept of normal weight obesity. Prog Cardiovasc Dis 2014; 56: 426-433
• 8 Poulain-Godefroy O, Lecoeur C, Pattou F. et al. Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol-Regul Integr Comp Physiol 2008; 295: R1-R7
• 9 Zhang T, Fang Z, Linghu K-G. et al. Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes. Br J Pharmacol 2020; 177: 4645-4665
• 10 Aouadi M, Tencerova M, Vangala P. et al. Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci 2013; 110: 8278-8283
• 11 Shan B, Wang X, Wu Y. et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 2017; 18: 519-529
• 12 Odegaard JI, Ricardo-Gonzalez RR, Goforth MH. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 2007; 447: 1116-1120
• 13 Kratz M, Hagman DK, Kuzma JN. et al. Improvements in glycemic control after gastric bypass occur despite persistent adipose tissue inflammation. Obesity 2016; 24: 1438-1445
• 14 Capel F, Klimčáková E, Viguerie N. et al. Macrophages and adipocytes in human obesity: Adipose tissue gene expression and insulin sensitivity during calorie restriction and weight stabilization. Diabetes 2009; 58: 1558-1567
• 15 Zamarron BF, Mergian TA, Cho KW. et al. Macrophage proliferation sustains adipose tissue inflammation in formerly obese mice. Diabetes 2016; 66: 392-406
• 16 Kosteli A, Sugaru E, Haemmerle G. et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 2010; 120: 3466-3479
• 17 Farias TDSM, Paixao RID, Cruz MM. et al. Melatonin supplementation attenuates the pro-inflammatory adipokines expression in visceral fat from obese mice induced by a high-fat diet. Cells 2019; 8: 1041
• 18 de Farias TDSM, Cruz MM, de Sa RCDC. et al Melatonin supplementation decreases hypertrophic obesity and inflammation induced by high-fat diet in mice. Front Endocrinol 2019; 10: 750
• 19 Wilding JPH, Batterham RL, Calanna S. et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021; 384: 989-1002
• 20 Martins FF, Marinho TS, Cardoso LEM. et al. Semaglutide (GLP-1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice. Cell Biochem Funct 2022; 40: 903-913
• 21 Xu X, Grijalva A, Skowronski A. et al. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 2013; 18: 816-830
• 22 Kratz M, Coats BR, Hisert KB. et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab 2014; 20: 614-625
• 23 Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC. et al. Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep 2017; 20: 3149-3161
• 24 Jaitin DA, Adlung L, Thaiss CA. et al. Lipid-associated macrophages control metabolic homeostasis in a trem2-dependent manner. Cell 2019; 178: 686-698.e14
• 25 Ulland TK, Song WM, Huang SC-C. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 2017; 170: 649-663.e13
• 26 Ulland TK, Colonna M. TREM2 — a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 2018; 14: 667-675
• 27 Patterson MT, Firulyova M, Xu Y. et al Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis. 2022 2022.11.28.518255
• 28 Gabriel TL, Tol MJ, Ottenhof R. et al. Lysosomal stress in obese adipose tissue macrophages contributes to MITF-dependent Gpnmb Induction. Diabetes 2014; 63: 3310-3323
• 29 Weterman MA, Ajubi N, van Dinter IM. et al. nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer 1995; 60: 73-81
• 30 Lazaratos A-M, Annis MG, Siegel PM. GPNMB: A potent inducer of immunosuppression in cancer. Oncogene 2022; 41: 4573-4590
• 31 Maric G, Rose AA, Annis MG. et al. Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer. OncoTargets Ther 2013; 6: 839-852
• 32 Saade M, Araujo de Souza G, Scavone C. et al. The Role of GPNMB in Inflammation. Front Immunol 2021; 12: 674739
• 33 Chung J-S, Ramani V, Kobayashi M. et al. DC-HIL/Gpnmb is a negative regulator of tumor response to immune checkpoint inhibitors. Clin Cancer Res 2020; 26: 1449-1459
• 34 Suda M, Shimizu I, Katsuumi G. et al. Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells. Sci Rep 2022; 12: 6522
• 35 Biswas KB, Takahashi A, Mizutani Y. et al. GPNMB is expressed in human epidermal keratinocytes but disappears in the vitiligo lesional skin. Sci Rep 2020; 10: 4930
• 36 Howell GR, Libby RT, Marchant JK. et al. Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1. BMC Genet 2007; 8: 45
• 37 Järve A, Mühlstedt S, Qadri F. et al. Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma protein B in myocardial infarction. FASEB J 2017; 31: 556-568
• 38 Nickl B, Qadri F, Bader M. Role of Gpnmb in atherosclerosis of female mice. Biochem Biophys Res Commun 2022; 621: 20-24
• 39 Anderson MG, Smith RS, Hawes NL. et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat Genet 2002; 30: 81-85
• 40 Mo J-S, Anderson MG, Gregory M. et al. By altering ocular immune privilege, bone marrow–derived cells pathogenically contribute to DBA/2J pigmentary glaucoma. J Exp Med 2003; 197: 1335-1344
• 41 John SW, Smith RS, Savinova OV. et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci 1998; 39: 951-962
• 42 Rahman OU, Kim J, Mahon C. et al. Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families. Genes Genomics 2021; 43: 471-478
• 43 Onoufriadis A, Hsu C-K, Eide CR. et al. Semidominant GPNMB mutations in amyloidosis cutis dyschromica. J Invest Dermatol 2019; 139: 2550-2554.e9
• 44 GPNMB - Transmembrane glycoprotein NMB - Homo sapiens (Human) | UniProtKB | UniProt. Im Internet: https://www.uniprot.org/uniprotkb/Q14956/entry Stand: 04.07.2023
• 45 Gpnmb - Transmembrane glycoprotein NMB - Mus musculus (Mouse) | UniProtKB | UniProt. . Im Internet: https://www.uniprot.org/uniprotkb/Q99P91/entry Stand: 04.07.2023
• 46 Shikano S, Bonkobara M, Zukas PK. et al. Molecular cloning of a dendritic cell-associated transmembrane protein, DC-HIL, that promotes RGD-dependent adhesion of endothelial cells through recognition of heparan sulfate proteoglycans. J Biol Chem 2001; 276: 8125-8134
• 47 Selim AA. Osteoactivin bioinformatic analysis: Prediction of novel functions, structural features, and modes of action. Med Sci Monit. 2009. 15. MT19-MT33
• 48 Singh M, Del Carpio-Cano F, Belcher JY. et al. Functional roles of osteoactivin in normal and disease processes. Crit Rev Eukaryot Gene Expr 2010; 20: 341-357
• 49 Hoashi T, Sato S, Yamaguchi Y. et al. Glycoprotein nonmetastatic melanoma protein b, a melanocytic cell marker, is a melanosome-specific and proteolytically released protein. FASEB J 2010; 24: 1616-1629
• 50 Abdelmagid S, Barbe M, Rico M. et al. Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function. Exp Cell Res 2008; 314: 2334-2351
• 51 Kuan C-T, Wakiya K, Dowell JM. et al. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res 2006; 12: 1970-1982
• 52 Ripoll VM, Irvine KM, Ravasi T. et al. Gpnmb is induced in macrophages by IFN-γ and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses. J Immunol 2007; 178: 6557-6566
• 53 Zhou LT, Liu FY, Li Y. et al. Gpnmb/osteoactivin, an attractive target in cancer immunotherapy. Neoplasma 2012; 59: 1-5
• 54 Li B, Castano AP, Hudson TE. et al. The melanoma-associated transmembrane glycoprotein Gpnmb controls trafficking of cellular debris for degradation and is essential for tissue repair. FASEB J 2010; 24: 4767-4781
• 55 Ripoll VM, Meadows NA, Raggatt L-J. et al. Microphthalmia transcription factor regulates the expression of the novel osteoclast factor GPNMB. Gene 2008; 413: 32-41
• 56 Boada-Romero E, Martinez J, Heckmann BL. et al. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol 2020; 21: 398-414
• 57 Campana L, Starkey Lewis PJ, Pellicoro A. et al. The STAT3–IL-10–IL-6 pathway Is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J Immunol 2018; 200: 1169-1187
• 58 Rose AAN, Annis MG, Dong Z. et al. ADAM10 releases a soluble form of the GPNMB/Osteoactivin extracellular domain with angiogenic properties. PloS One 2010; 5: e12093
• 59 Taya M, Hammes SR. Glycoprotein non-metastatic melanoma protein B (GPNMB) and cancer: A novel potential therapeutic target. Steroids 2018; 133: 102-107
• 60 Tanaka H, Shimazawa M, Kimura M. et al. The potential of GPNMB as novel neuroprotective factor in amyotrophic lateral sclerosis. Sci Rep 2012; 2: 573
• 61 Yu B, Sondag GR, Malcuit C. et al. Macrophage-associated osteoactivin/GPNMB mediates mesenchymal stem cell survival, proliferation, and migration via a CD44-dependent mechanism. J Cell Biochem 2016; 117: 1511-1521
• 62 Nakano Y, Suzuki Y, Takagi T. et al. Glycoprotein nonmetastatic melanoma protein B (GPNMB) as a novel neuroprotective factor in cerebral ischemia–reperfusion injury. Neuroscience 2014; 277: 123-131
• 63 Ono Y, Tsuruma K, Takata M. et al. Glycoprotein nonmetastatic melanoma protein B extracellular fragment shows neuroprotective effects and activates the PI3K/Akt and MEK/ERK pathways via the Na+/K+-ATPase. Sci Rep 2016; 6: 23241
• 64 Gutknecht M, Geiger J, Joas S. et al. The transcription factor MITF is a critical regulator of GPNMB expression in dendritic cells. Cell Commun Signal CCS 2015; 13: 19
• 65 Loftus SK, Antonellis A, Matera I. et al. Gpnmb is a melanoblast-expressed, MITF-dependent gene. Pigment Cell Melanoma Res 2009; 22: 99-110
• 66 Tol MJ, van der Lienden MJC, Gabriel TL. et al. HEPES activates a MiT/TFE-dependent lysosomal-autophagic gene network in cultured cells: A call for caution. Autophagy 2018; 14: 437-449
• 67 Boot RG, Bussink AP, Verhoek M. et al. Marked differences in tissue-specific expression of chitinases in mouse and man. J Histochem Cytochem 2005; 53: 1283-1292
• 68 Schutyser E, Richmond A, Van Damme J. Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes. J Leukoc Biol 2005; 78: 14-26
• 69 Kramer G, Wegdam W, Donker-Koopman W. et al. Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models. FEBS Open Bio 2016; 6: 902-913
• 70 Zigdon H, Savidor A, Levin Y. et al. Identification of a biomarker in cerebrospinal fluid for neuronopathic forms of Gaucher disease. PLoS One 2015; 10: e0120194
• 71 Xu Y-H, Jia L, Quinn B. et al. Global gene expression profile progression in Gaucher disease mouse models. BMC Genomics 2011; 12: 20
• 72 Murugesan V, Liu J, Yang R. et al. Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease. Blood Cells Mol Dis 2018; 68: 47-53
• 73 van der Lienden MJC, Gaspar P, Boot R. et al. Glycoprotein non-metastatic protein B: An emerging biomarker for lysosomal dysfunction in macrophages. Int J Mol Sci 2018; 20: 66
• 74 Marques ARA, Gabriel TL, Aten J. et al. Gpnmb Is a potential marker for the visceral pathology in Niemann-Pick type C disease. PLoS One 2016; 11: e0147208
• 75 Rodriguez-Gil JL, Baxter LL, Watkins-Chow DE. et al. Transcriptome of HPβCD-treated Niemann-Pick disease type C1 cells highlights GPNMB as a biomarker for therapeutics. Hum Mol Genet 2021; 30: 2456-2468
• 76 Eskes ECB, van der Lienden MJC, Sjouke B. et al. Glycoprotein non-metastatic protein B (GPNMB) plasma values in patients with chronic visceral acid sphingomyelinase deficiency. Mol Genet Metab 2023; 139: 107631
• 77 Yu L, McPhee CK, Zheng L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010; 465: 942-946
• 78 Betz C, Hall MN. Where is mTOR and what is it doing there?. J Cell Biol 2013; 203: 563-574
• 79 Kinghorn KJ, Grönke S, Castillo-Quan JI. et al. A drosophila model of neuronopathic Gaucher disease demonstrates lysosomal-autophagic defects and altered mTOR signalling and is functionally rescued by rapamycin. J Neurosci 2016; 36: 11654-11670
• 80 Kim J, Kim SH, Kang H. et al. TFEB–GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response. Nat Metab 2021; 3: 410-427
• 81 Katayama A, Nakatsuka A, Eguchi J. et al. Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. Sci Rep 2015; 5: 16920
• 82 Zambonelli P, Gaffo E, Zappaterra M. et al. Transcriptional profiling of subcutaneous adipose tissue in Italian large white pigs divergent for backfat thickness. Anim Genet 2016; 47: 306-323
• 83 Nickl B, Qadri F, Bader M. Anti-inflammatory role of Gpnmb in adipose tissue of mice. Sci Rep 2021; 11: 19614
• 84 Prabata A, Ikeda K, Rahardini EP. et al. GPNMB plays a protective role against obesity-related metabolic disorders by reducing macrophage inflammatory capacity. J Biol Chem 2021; 297: 101232
• 85 Buettner R, Parhofer KG, Woenckhaus M. et al. Defining high-fat-diet rat models: Metabolic and molecular effects of different fat types. J Mol Endocrinol 36: 485-501
• 86 Gong X-M, Li Y-F, Luo J. et al. Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. Nat Metab 2019; 1: 570-583
• 87 Li W, Guo J, Chen J. et al. Identification of immune infiltration and the potential biomarkers in diabetic peripheral neuropathy through bioinformatics and machine learning methods. Biomolecules 2023; 13: 39
• 88 Qin T, Xi X, Wu Z. Downregulation of glycoprotein non-metastatic melanoma protein B prevents high glucose-induced angiogenesis in diabetic retinopathy. Mol Cell Biochem 2023; 478: 697-706
• 89 Huo D, Liu Y-Y, Zhang C. et al. Serum glycoprotein non-metastatic melanoma protein B (GPNMB) level as a potential biomarker for diabetes mellitus-related cataract: A cross-sectional study. Front Endocrinol 2023; 14: 1110337