A progranulin egy újonnan felfedezett multifunkcionális glikoprotein, amely összefüggésben van az elhízás és a cukorbetegség kialakulásával. A progranulin a tumornekrózisfaktor-α endogén antagonistája, kompetitíven kötődik annak receptorához, így antiinflammatoricus aktivitással rendelkezik. Érdekes módon korábbi tanulmányok kimutatták, hogy a progranulin szérumszintje emelkedett a cukorbetegekben, és összefüggésbe hozták a cukorbetegség bizonyos komplikációival, beleértve a micro- és macroangiopathiát, a macroalbuminuriát és a csökkent vesefunkciót. Továbbá a hyperprogranulinaemia közrejátszhat az elhízáshoz társuló inzulinrezisztencia patogenezisében. A cikkben összefoglaljuk a jelenleg elérhető adatokat a progranulinnak – mint új markernek – a szénhidrát-metabolizmusban és a gyulladásban betöltött szerepére vonatkozóan. Orv Hetil. 2019; 160(25): 973–979.
Weisman A, Fazli GS, Johns A, et al. Evolving trends in the epidemiology, risk factors, and prevention of type 2 diabetes: a review. Can J Cardiol. 2018; 34: 552–564.
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018; 14: 88–98.
Kalofoutis C, Piperi C, Kalofoutis A, et al. Type II diabetes mellitus and cardiovascular risk factors: current therapeutic approaches. Exp Clin Cardiol. 2007; 12: 17–28.
Veldman BA, Vervoort G. Pathogenesis of renal microvascular complications in diabetes mellitus. Neth J Med. 2002; 60: 390–396.
Khalil H. Diabetes microvascular complications – a clinical update. Diabetes Metab Syndr. 2017; 11(Suppl 1): S133–S139.
Nunemaker CS. Considerations for defining cytokine dose, duration, and milieu that are appropriate for modeling chronic low-grade inflammation in type 2 diabetes. J Diabetes Res. 2016; 2016: 2846570.
Dorcely B, Katz K, Jagannathan R, et al. Novel biomarkers for prediabetes, diabetes, and associated complications. Diabetes Metab Syndr Obes. 2017; 10: 345–361.
Márk L, Harangi M, Paragh G. The labyrinth of residual risk: reduction of the remaining lipid and inflammation risk in the prevention of atherosclerosis. [A residualis kockázat útvesztői: a maradék lipid és gyulladásos kockázat csökkentése az atherosclerosis prevenciójában.] Orv Hetil. 2018; 159: 124–130. [Hungarian]
Babik B, Peták F, Agócs S, et al. Diabetes mellitus: endothelial dysfunction and changes in hemostasis. [Diabetes mellitus: endotheldiszfunkció és haemostasiselváltozások.] Orv Hetil. 2018; 159: 1335–1345. [Hungarian]
Bateman A, Bennett HP. Granulins: the structure and function of an emerging family of growth factors. J Endocrinol. 1998; 158: 145–151.
Plowman GD, Green JM, Neubauer MG, et al. The epithelin precursor encodes two proteins with opposing activities on epithelial cell growth. J Biol Chem. 1992; 267: 13073–13078.
Zhou J, Gao G, Crabb JW, et al. Purification of an autocrine growth factor homologous with mouse epithelin precursor from a highly tumorigenic cell line. J Biol Chem. 1993; 268: 10863–10869.
Baba T, Hoff HB 3rd, Nemoto H, et al. Acrogranin, an acrosomal cysteine-rich glycoprotein, is the precursor of the growth-modulating peptides, granulins, and epithelins, and is expressed in somatic as well as male germ cells. Mol Reprod Dev. 1993; 34: 233–243.
Bhandari V, Palfree RG, Bateman A. Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains. Proc Natl Acad Sci U S A 1992; 89: 1715–1719.
He Z, Bateman A. Progranulin gene expression regulates epithelial cell growth and promotes tumor growth in vivo. Cancer Res. 1999; 59: 3222–3229.
Koo DH, Park CY, Lee ES, et al. Progranulin as a prognostic biomarker for breast cancer recurrence in patients who had hormone receptor-positive tumors: a cohort study. PLoS ONE 2012; 7: e39880.
Han JJ, Yu M, Houston N, et al. Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers. Gynecol Oncol. 2011; 120: 5–10.
Demorrow S. Progranulin: a novel regulator of gastrointestinal cancer progression. Transl Gastrointest Cancer 2013; 2: 145–151.
Donald CD, Laddu A, Chandham P, et al. Expression of progranulin and the epithelin/granulin precursor acrogranin correlates with neoplastic state in renal epithelium. Anticancer Res. 2001; 21: 3739–3742.
Hrabal R, Chen Z, James S, et al. The hairpin stack fold, a novel protein architecture for a new family of protein growth factors. Nat Struct Biol. 1996; 3: 747–752.
He Z, Ong CH, Halper J, et al. Progranulin is a mediator of the wound response. Nat Med. 2003; 9: 225–229.
Tolkatchev D, Ng A, Vranken W, et al. Design and solution structure of a well-folded stack of two β-hairpins based on the amino-terminal fragment of human granulin A. Biochemistry 2000; 39: 2878–2886.
Bhandari V, Bateman A. Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun. 1992; 188: 57–63.
Bucan M, Gatalica B, Baba T, et al. Mapping of GRN, the gene encoding the granulin/epithelin precursor (acrogranin), to mouse Chromosome 11. Mamm Genome 1996; 7: 704–705.
Bhandari V, Giaid A, Bateman A. The complementary deoxyribonucleic acid sequence, tissue distribution, and cellular localization of the rat granulin precursor. Endocrinology 1993; 133: 2682–2689.
Daniel R, He Z, Carmichael KP, et al. Cellular localization of gene expression for progranulin. J Histochem Cytochem. 2000; 48: 999–1009.
Finch N, Baker M, Crook R, et al. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 2009; 132(Pt 3): 583–591.
Martens LH, Zhang J, Barmada SJ, et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012; 122: 3955–3959.
Zheng Y, Brady OA, Meng PS, et al. C-terminus of progranulin interacts with the beta-propeller region of sortilin to regulate progranulin trafficking. PLoS ONE 2011; 6: e21023.
Zhu J, Nathan C, Jin W, et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 2002; 111: 867–878.
Tang W, Lu Y, Tian QY, et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 2011; 332: 478–484.
Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011; 34: 505–513.
Nguyen AD, Nguyen TA, Cenik B, et al. Secreted progranulin is a homodimer and is not a component of high density lipoproteins (HDL). J Biol Chem. 2013; 288: 8627–8635.
Huang K, Chen A, Zhang X, et al. Progranulin is preferentially expressed in patients with psoriasis vulgaris and protects mice from psoriasis-like skin inflammation. Immunology 2015; 145: 279–287.
Yamamoto Y, Takemura M, Serrero G, et al. Increased serum GP88 (progranulin) concentrations in rheumatoid arthritis. Inflammation 2014; 37: 1806–1813.
Zhou M, Tang W, Fu Y, et al. Progranulin protects against renal ischemia/reperfusion injury in mice. Kidney Int. 2015; 87: 918–929.
Nicoletto BB, Canani LH. The role of progranulin in diabetes and kidney disease. Diabetol Metab Syndr. 2015; 7: 117.
Langenberg C, Sharp SJ, Schulze MB, et al. Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study. PLoS Med. 2012; 9: e1001230.
Youn BS, Bang SI, Klöting N, et al. Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue. Diabetes 2009; 58: 627–636.
Matsubara T, Mita A, Minami K, et al. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metab. 2012; 15: 38–50.
Carecchio M, Fenoglio C, De Riz M, et al. Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic mild cognitive impairment converted to Alzheimer’s disease. J Neurol Sci. 2009; 287: 291–293.
Shafaei A, Marjani A, Khoshnia M. Serum progranulin levels in type 2 diabetic patients with metabolic syndrome. Rom J Intern Med. 2016; 54: 211–216.
Faerch K, Vaag A, Witte DR, et al. Predictors of future fasting and 2-h post-OGTT plasma glucose levels in middle-aged men and women – the Inter99 study. Diabet Med. 2009; 26: 377–383.
Qu H, Deng H, Hu Z. Plasma progranulin concentrations are increased in patients with type 2 diabetes and obesity and correlated with insulin resistance. Mediators Inflamm. 2013; 2013: 360190.
Xu L, Zhou B, Li H, et al. Serum levels of progranulin are closely associated with microvascular complication in type 2 diabetes. Dis Markers 2015; 2015: 357279.