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Hepatic heparan sulfate is a master regulator of hepcidin expression and iron homeostasis in human hepatocytes and mice.
Poli, Maura; Anower-E-Khuda, Ferdous; Asperti, Michela; Ruzzenenti, Paola; Gryzik, Magdalena; Denardo, Andrea; Gordts, Philip L S M; Arosio, Paolo; Esko, Jeffrey D.
Afiliação
  • Poli M; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy. Electronic address: maura.poli@unibs.it.
  • Anower-E-Khuda F; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093.
  • Asperti M; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Ruzzenenti P; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Gryzik M; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Denardo A; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Gordts PLSM; Glycobiology Research and Training Center, University of California San Diego, La Jolla, California 92093; Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California 92093.
  • Arosio P; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy.
  • Esko JD; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093; Glycobiology Research and Training Center, University of California San Diego, La Jolla, California 92093.
J Biol Chem ; 294(36): 13292-13303, 2019 09 06.
Article em En | MEDLINE | ID: mdl-31315930
Hepcidin is a liver-derived peptide hormone that controls systemic iron homeostasis. Its expression is regulated by the bone morphogenetic protein 6 (BMP6)/SMAD1/5/8 pathway and by the proinflammatory cytokine interleukin 6 (IL6). Proteoglycans that function as receptors of these signaling proteins in the liver are commonly decorated by heparan sulfate, but the potential role of hepatic heparan sulfate in hepcidin expression and iron homeostasis is unclear. Here, we show that modulation of hepatic heparan sulfate significantly alters hepcidin expression and iron metabolism both in vitro and in vivo Specifically, enzymatic removal of heparan sulfate from primary human hepatocytes, CRISPR/Cas9 manipulation of heparan sulfate biosynthesis in human hepatoma cells, or pharmacological manipulation of heparan sulfate-protein interactions using sodium chlorate or surfen dramatically reduced baseline and BMP6/SMAD1/5/8-dependent hepcidin expression. Moreover inactivation of the heparan sulfate biosynthetic gene N-deacetylase and N-sulfotransferase 1 (Ndst1) in murine hepatocytes (Ndst1f/fAlbCre+) reduced hepatic hepcidin expression and caused a redistribution of systemic iron, leading to iron accumulation in the liver and serum of mice. Manipulation of heparan sulfate had a similar effect on IL6-dependent hepcidin expression in vitro and suppressed IL6-mediated iron redistribution induced by lipopolysaccharide in vivo These results provide compelling evidence that hepatocyte heparan sulfate plays a key role in regulating hepcidin expression and iron homeostasis in mice and in human hepatocytes.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hepatócitos / Hepcidinas / Heparitina Sulfato / Homeostase / Ferro Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hepatócitos / Hepcidinas / Heparitina Sulfato / Homeostase / Ferro Limite: Animals / Humans Idioma: En Revista: J Biol Chem Ano de publicação: 2019 Tipo de documento: Article