Skip to main content

Advertisement

SpringerLink
Log in

Dichotomic role of heparanase in a murine model of metabolic syndrome

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters β-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

Not applicable.

Abbreviations

ECM:

Extracellular matrix

HS:

Heparan sulfate

AGE:

Advanced glycation end products

HFD:

High-fat diet

CD:

Control diet

Hpse-KO:

Heparanase-deficient mice

sFA:

Saturated fatty acids

uFA:

Unsaturated fatty acids

References

  1. Huang G, Greenspan DS (2012) ECM roles in the function of metabolic tissues. Trends Endocrinol Metab 23(1):16–22. https://doi.org/10.1016/j.tem.2011.09.006

    Article  CAS  PubMed  Google Scholar 

  2. Ussar S, Bezy O, Bluher M, Kahn CR (2012) Glypican-4 enhances insulin signaling via interaction with the insulin receptor and serves as a novel adipokine. Diabetes 61(9):2289–2298

    Article  CAS  Google Scholar 

  3. Yamashita Y, Nakada S, Yoshihara T, Nara T, Furuya N, Miida T, Hattori N, Arikawa-Hirasawa E (2018) Perlecan, a heparan sulfate proteoglycan, regulates systemic metabolism with dynamic changes in adipose tissue and skeletal muscle. Sci Rep 8(1):7766. https://doi.org/10.1038/s41598-018-25635-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Townsend SE, Gannon M (2019) Extracellular matrix-associated factors play critical roles in regulating pancreatic beta-cell proliferation and survival. Endocrinology 160(8):1885–1894. https://doi.org/10.1210/en.2019-00206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kang L, Ayala JE, Lee-Young RS, Zhang Z, James FD, Neufer PD, Pozzi A, Zutter MM, Wasserman DH (2011) Diet-induced muscle insulin resistance is associated with extracellular matrix remodeling and interaction with integrin alpha2beta1 in mice. Diabetes 60(2):416–426. https://doi.org/10.2337/db10-1116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Abu El-Asrar AM, Alam K, Nawaz MI, Mohammad G, Van den Eynde K, Siddiquei MM, Mousa A, De Hertogh G, Geboes K, Opdenakker G (2015) Upregulated expression of heparanase in the vitreous of patients with proliferative diabetic retinopathy originates from activated endothelial cells and leukocytes. Invest Ophthalmol Vis Sci 56(13):8239–8247. https://doi.org/10.1167/iovs.15-18025

    Article  CAS  PubMed  Google Scholar 

  7. Baker AB, Chatzizisis YS, Beigel R, Jonas M, Stone BV, Coskun AU, Maynard C, Rogers C, Koskinas KC, Feldman CL, Stone PH, Edelman ER (2010) Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine. Atherosclerosis 213(2):436–442

    Article  CAS  Google Scholar 

  8. Gil N, Goldberg R, Neuman T, Garsen M, Zcharia E, Rubinstein AM, van Kuppevelt T, Meirovitz A, Pisano C, Li JP, van der Vlag J, Vlodavsky I, Elkin M (2012) Heparanase is essential for the development of diabetic nephropathy in mice. Diabetes 61(1):208–216. https://doi.org/10.2337/db11-1024

    Article  CAS  PubMed  Google Scholar 

  9. Goldberg R, Rubinstein AM, Gil N, Hermano E, Li JP, van der Vlag J, Atzmon R, Meirovitz A, Elkin M (2014) Role of heparanase-driven inflammatory cascade in pathogenesis of diabetic nephropathy. Diabetes 63(12):4302–4313

    Article  CAS  Google Scholar 

  10. Simeonovic CJ, Popp SK, Brown DJ, Li FJ, Lafferty ARA, Freeman C, Parish CR (2020) Heparanase and type 1 diabetes. Adv Exp Med Biol 1221:607–630. https://doi.org/10.1007/978-3-030-34521-1_24

    Article  CAS  PubMed  Google Scholar 

  11. Simeonovic CJ, Popp SK, Starrs LM, Brown DJ, Ziolkowski AF, Ludwig B, Bornstein SR, Wilson JD, Pugliese A, Kay TWH, Thomas HE, Loudovaris T, Choong FJ, Freeman C, Parish CR (2018) Loss of intra-islet heparan sulfate is a highly sensitive marker of type 1 diabetes progression in humans. PLoS ONE 13(2):e0191360. https://doi.org/10.1371/journal.pone.0191360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Simeonovic CJ, Ziolkowski AF, Wu Z, Choong FJ, Freeman C, Parish CR (2013) Heparanase and autoimmune diabetes. Front Immunol 4:471. https://doi.org/10.3389/fimmu.2013.00471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang D, Wang F, Lal N, Chiu AP, Wan A, Jia J, Bierende D, Flibotte S, Sinha S, Asadi A, Hu X, Taghizadeh F, Pulinilkunnil T, Nislow C, Vlodavsky I, Johnson JD, Kieffer TJ, Hussein B, Rodrigues B (2017) Heparanase overexpression induces glucagon resistance and protects animals from chemically induced diabetes. Diabetes 66(1):45–57. https://doi.org/10.2337/db16-0761

    Article  CAS  PubMed  Google Scholar 

  14. Ziolkowski AF, Popp SK, Freeman C, Parish CR, Simeonovic CJ (2012) Heparan sulfate and heparanase play key roles in mouse beta cell survival and autoimmune diabetes. J Clin Invest 122(1):132–141. https://doi.org/10.1172/JCI46177

    Article  CAS  PubMed  Google Scholar 

  15. An XF, Zhou L, Jiang PJ, Yan M, Huang YJ, Zhang SN, Niu YF, Ten SC, Yu JY (2011) Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor. Mol Cell Biochem 354(1–2):47–55

    Article  CAS  Google Scholar 

  16. Masola V, Gambaro G, Tibaldi E, Onisto M, Abaterusso C, Lupo A (2011) Regulation of heparanase by albumin and advanced glycation end products in proximal tubular cells. Biochim Biophys Acta 1813:1475–1482. https://doi.org/10.1016/j.bbamcr.2011.05.004

    Article  CAS  PubMed  Google Scholar 

  17. Maxhimer JB, Somenek M, Rao G, Pesce CE, Baldwin D Jr, Gattuso P, Schwartz MM, Lewis EJ, Prinz RA, Xu X (2005) Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients. Diabetes 54(7):2172–2178

    Article  CAS  Google Scholar 

  18. Qin Q, Niu J, Wang Z, Xu W, Qiao Z, Gu Y (2013) Heparanase induced by advanced glycation end products (AGEs) promotes macrophage migration involving RAGE and PI3K/AKT pathway. Cardiovasc Diabetol 12(1):37

    Article  CAS  Google Scholar 

  19. Han J, Hiebert LM (2013) Alteration of endothelial proteoglycan and heparanase gene expression by high glucose, insulin and heparin. Vascul Pharmacol 59(3–4):112–118

    Article  CAS  Google Scholar 

  20. Qing Q, Zhang S, Chen Y, Li R, Mao H, Chen Q (2015) High glucose-induced intestinal epithelial barrier damage is aggravated by syndecan-1 destruction and heparanase overexpression. J Cell Mol Med. https://doi.org/10.1111/jcmm.12523

    Article  PubMed  PubMed Central  Google Scholar 

  21. Parish CR, Freeman C, Ziolkowski AF, He YQ, Sutcliffe EL, Zafar A, Rao S, Simeonovic CJ (2013) Unexpected new roles for heparanase in type 1 diabetes and immune gene regulation. Matrix Biol 32(5):228–233. https://doi.org/10.1016/j.matbio.2013.02.007

    Article  CAS  PubMed  Google Scholar 

  22. Eguchi K, Nagai R (2017) Islet inflammation in type 2 diabetes and physiology. J Clin Invest 127(1):14–23. https://doi.org/10.1172/JCI88877

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ying W, Fu W, Lee YS, Olefsky JM (2020) The role of macrophages in obesity-associated islet inflammation and beta-cell abnormalities. Nat Rev Endocrinol 16(2):81–90. https://doi.org/10.1038/s41574-019-0286-3

    Article  PubMed  Google Scholar 

  24. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107

    Article  CAS  Google Scholar 

  25. Nackiewicz D, Dan M, He W, Kim R, Salmi A, Rutti S, Westwell-Roper C, Cunningham A, Speck M, Schuster-Klein C, Guardiola B, Maedler K, Ehses JA (2014) TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6. Diabetologia 57(8):1645–1654

    Article  CAS  Google Scholar 

  26. Eheim A, Medrikova D, Herzig S (2014) Immune cells and metabolic dysfunction. Semin Immunopathol 36(1):13–25

    Article  CAS  Google Scholar 

  27. Marzban L (2015) New insights into the mechanisms of islet inflammation in type 2 diabetes. Diabetes 64(4):1094–1096. https://doi.org/10.2337/db14-1903

    Article  CAS  PubMed  Google Scholar 

  28. Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F, Yagi N, Ohto U, Kimoto M, Miyake K, Tobe K, Arai H, Kadowaki T, Nagai R (2012) Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab 15(4):518–533

    Article  CAS  Google Scholar 

  29. Ying W, Lee YS, Dong Y, Seidman JS, Yang M, Isaac R, Seo JB, Yang BH, Wollam J, Riopel M, McNelis J, Glass CK, Olefsky JM, Fu W (2019) Expansion of islet-resident macrophages leads to inflammation affecting beta cell proliferation and function in obesity. Cell Metab 29(2):457–474.e455. https://doi.org/10.1016/j.cmet.2018.12.003

    Article  CAS  PubMed  Google Scholar 

  30. Ehses JA, Perren A, Eppler E, Ribaux P, Pospisilik JA, Maor-Cahn R, Gueripel X, Ellingsgaard H, Schneider MK, Biollaz G, Fontana A, Reinecke M, Homo-Delarche F, Donath MY (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56(9):2356–2370

    Article  CAS  Google Scholar 

  31. Westwell-Roper CY, Ehses JA, Verchere CB (2014) Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 63(5):1698–1711. https://doi.org/10.2337/db13-0863

    Article  CAS  PubMed  Google Scholar 

  32. Hermano E, Goldberg R, Rubinstein AM, Sonnenblick A, Maly B, Nahmias D, Li JP, Bakker MAH, van der Vlag J, Vlodavsky I, Peretz T, Elkin M (2019) Heparanase accelerates obesity-associated breast cancer progression. Cancer Res 79(20):5342–5354. https://doi.org/10.1158/0008-5472.CAN-18-4058

    Article  CAS  PubMed  Google Scholar 

  33. Blich M, Golan A, Arvatz G, Sebbag A, Shafat I, Sabo E, Cohen-Kaplan V, Petcherski S, Avniel-Polak S, Eitan A, Hammerman H, Aronson D, Axelman E, Ilan N, Nussbaum G, Vlodavsky I (2013) Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progression. Arterioscler Thromb Vasc Biol 33(2):e56–65. https://doi.org/10.1161/ATVBAHA.112.254961

    Article  CAS  PubMed  Google Scholar 

  34. Hermano E, Meirovitz A, Meir K, Nussbaum G, Appelbaum L, Peretz T, Elkin M (2014) Macrophage polarization in pancreatic carcinoma: role of heparanase enzyme. J Natl Cancer Inst 106(12):dju332

    Article  Google Scholar 

  35. Lerner I, Hermano E, Zcharia E, Rodkin D, Bulvik R, Doviner V, Rubinstein AM, Ishai-Michaeli R, Atzmon R, Sherman Y, Meirovitz A, Peretz T, Vlodavsky I, Elkin M (2011) Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice. J Clin Invest 121(5):1709–1721

    Article  CAS  Google Scholar 

  36. Masola V, Zaza G, Bellin G, Dall'Olmo L, Granata S, Vischini G, Secchi MF, Lupo A, Gambaro G, Onisto M (2018) Heparanase regulates the M1 polarization of renal macrophages and their crosstalk with renal epithelial tubular cells after ischemia/reperfusion injury. FASEB J 32(2):742–756. https://doi.org/10.1096/fj.201700597R

    Article  CAS  PubMed  Google Scholar 

  37. Zcharia E, Jia J, Zhang X, Baraz L, Lindahl U, Peretz T, Vlodavsky I, Li JP (2009) Newly generated heparanase knock-out mice unravel co-regulation of heparanase and matrix metalloproteinases. PLoS ONE 4(4):e5181

    Article  Google Scholar 

  38. Montgomery MK, Hallahan NL, Brown SH, Liu M, Mitchell TW, Cooney GJ, Turner N (2013) Mouse strain-dependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56(5):1129–1139

    Article  CAS  Google Scholar 

  39. Pettersson US, Walden TB, Carlsson PO, Jansson L, Phillipson M (2012) Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS ONE 7(9):e46057. https://doi.org/10.1371/journal.pone.0046057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu G, Qin Q, Yang M, Qiao Z, Gu Y, Niu J (2017) Heparanase-driven inflammation from the AGEs-stimulated macrophages changes the functions of glomerular endothelial cells. Diabetes Res Clin Pract 124:30–40. https://doi.org/10.1016/j.diabres.2016.12.016

    Article  CAS  PubMed  Google Scholar 

  41. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. https://doi.org/10.1172/JCI28898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cassinelli G, Dal Bo L, Favini E, Cominetti D, Pozzi S, Tortoreto M, De Cesare M, Lecis D, Scanziani E, Minoli L, Naggi A, Vlodavsky I, Zaffaroni N, Lanzi C (2018) Supersulfated low-molecular weight heparin synergizes with IGF1R/IR inhibitor to suppress synovial sarcoma growth and metastases. Cancer Lett 415:187–197. https://doi.org/10.1016/j.canlet.2017.12.009

    Article  CAS  PubMed  Google Scholar 

  43. Goldberg R, Sonnenblick A, Hermano E, Hamburger T, Meirovitz A, Peretz T, Elkin M (2017) Heparanase augments insulin receptor signaling in breast carcinoma. Oncotarget 8(12):19403–19412. https://doi.org/10.18632/oncotarget.14292

    Article  PubMed  Google Scholar 

  44. Purushothaman A, Babitz SK, Sanderson RD (2012) Heparanase enhances the insulin receptor signaling pathway to activate ERK in multiple myeloma. J Biol Chem 287(49):41288–41296

    Article  CAS  Google Scholar 

  45. Elkin M, Ilan N, Ishai-Michaeli R, Friedmann Y, Papo O, Pecker I, Vlodavsky I (2001) Heparanase as mediator of angiogenesis: mode of action. FASEB J 15(9):1661–1663. https://doi.org/10.1096/fj.00-0895fje

    Article  CAS  PubMed  Google Scholar 

  46. Ramani VC, Purushothaman A, Stewart MD, Thompson CA, Vlodavsky I, Au JL, Sanderson RD (2013) The heparanase/syndecan-1 axis in cancer: mechanisms and therapies. FEBS J 280(10):2294–2306

    Article  CAS  Google Scholar 

  47. Song WY, Jiang XH, Ding Y, Wang Y, Zhou MX, Xia Y, Zhang CY, Yin CC, Qiu C, Li K, Sun P, Han X (2020) Inhibition of heparanase protects against pancreatic beta cell death in streptozotocin-induced diabetic mice via reducing intra-islet inflammatory cell infiltration. Br J Pharmacol. https://doi.org/10.1111/bph.15183

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Prof. Danielle Melloul (Department of Endocrinology, Hadassah-Hebrew University Medical Center) for her continuous help and collaboration.

Funding

This study was supported by the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (Grant no. 663/16).

Author information

Author notes

  1. Esther Hermano, Françoise Carlotti, Alexia Abecassis contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Sharett Institute, Hadassah-Hebrew University Medical Center, 91120, Jerusalem, Israel

    Esther Hermano, Alexia Abecassis, Amichay Meirovitz, Ariel M. Rubinstein & Michael Elkin

  2. Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Françoise Carlotti & Ton J. Rabelink

  3. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden

    Jin-Ping Li

  4. Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel

    Israel Vlodavsky

  5. Hebrew University Medical School, 91120, Jerusalem, Israel

    Michael Elkin

Authors
  1. Esther Hermano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Françoise Carlotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexia Abecassis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amichay Meirovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ariel M. Rubinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Ping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Israel Vlodavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ton J. Rabelink
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Elkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.H., F.C., A.A., and A.M.R. conducted experiments; JP.L., I.V. generated/contributed experimental animals; E.H., F.C., A.M., T.J.R., M.E. analyzed data; E.H., F.C., T.J.R., M.E. designed research studies, E.H., F.C., A.M., I.V., T.J.R. reviewed and edited the manuscript. M.E. was responsible for conceptualization, study design, supervised the study, wrote the manuscript. M.E. is the guarantor of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Michael Elkin.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

All animal experiments were performed in accordance with the Hebrew University Institutional Animal Care and Use Committee.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hermano, E., Carlotti, F., Abecassis, A. et al. Dichotomic role of heparanase in a murine model of metabolic syndrome. Cell. Mol. Life Sci. 78, 2771–2780 (2021). https://doi.org/10.1007/s00018-020-03660-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-020-03660-2

Keywords

Search

Navigation