title: Heparanase Overexpression Reduces Hepcidin Expression, Affects Iron Homeostasis and Alters the Response to Inflammation.
abstract: Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS). To verify this hypothesis, we analyzed how the overexpression of heparanase, the HS degrading enzyme, modified hepcidin expression and iron homeostasis in hepatic cell lines and in transgenic mice. The results showed that transient and stable overexpression of heparanase in HepG2 cells caused a reduction of hepcidin expression and of SMAD5 phosphorylation. Interestingly, the clones showed also altered level of TfR1 and ferritin, indices of a modified iron homeostasis. The heparanase transgenic mice showed a low level of liver hepcidin, an increase of serum and liver iron with a decrease in spleen iron content. The hepcidin expression remained surprisingly low even after treatment with the inflammatory LPS. The finding that modification of HS structure mediated by heparanase overexpression affects hepcidin expression and iron homeostasis supports the hypothesis that HS participate in the mechanisms controlling hepcidin expression.
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine DMMT, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Asperti
authors.affiliation: Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, 32000, Haifa, Israel.
authors.forename: Tanja
authors.initials: T
authors.lastname: Stuemler
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine DMMT, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Poli
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine DMMT, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gryzik
authors.affiliation: Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, 32000, Haifa, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Lifshitz
authors.affiliation: Laboratory for Molecular Nutrition, Faculty of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Technion City, 32000, Haifa, Israel.
authors.forename: Esther G
authors.initials: EG
authors.lastname: Meyron-Holtz
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion- Israel Institute of Technology, Haifa, 31096, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Molecular Biology laboratory, Department of Molecular and Translational Medicine DMMT, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.
authors.forename: Paolo
authors.identifier: http://orcid.org/0000-0002-5343-8992
authors.initials: P
authors.lastname: Arosio
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics*; D056945:Hep G2 Cells; D006493:Heparin / Q000494:pharmacology; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D064451:Hepcidins / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D000099175:Heparanase
chemical_list: D055418:Bone Morphogenetic Protein 6; D005966:Glucuronidase; D006493:Heparin; D006497:Heparan Sulfate; D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron; D008070:Lipopolysaccharides; D051785:Smad Proteins; D000099175:Heparanase