title: Hepatic nerve growth factor induced by iron overload triggers defenestration in liver sinusoidal endothelial cells.
abstract: The fenestrations of liver sinusoidal endothelial cells (LSECs) play important roles in the exchange of macromolecules, solutes, and fluid between blood and surrounding liver tissues in response to hepatotoxic drugs, toxins, and oxidative stress. As excess iron is a hepatotoxin, LSECs may be affected by excess iron. In this study, we found a novel link between LSEC defenestration and hepatic nerve growth factor (NGF) in iron-overloaded mice. By Western blotting, NGF was highly expressed, whereas VEGF and HGF were not, and hepatic NGF mRNA levels were increased according to digital PCR. Immunohistochemically, NGF staining was localized in hepatocytes, while TrkA, an NGF receptor, was localized in LSECs. Scanning electron microscopy revealed LSEC defenestration in mice overloaded with iron as well as mice treated with recombinant NGF. Treatment with conditioned medium from iron-overloaded primary hepatocytes reduced primary LSEC fenestrations, while treatment with an anti-NGF neutralizing antibody or TrkA inhibitor, K252a, reversed this effect. However, iron-loaded medium itself did not reduce fenestration. In conclusion, iron accumulation induces NGF expression in hepatocytes, which in turn leads to LSEC defenestration via TrkA. This novel link between iron and NGF may aid our understanding of the development of chronic liver disease.
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Lynda
authors.initials: L
authors.lastname: Addo
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan. Electronic address: hiroki-t@asahikawa-med.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Toki
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.affiliation: Oncology Center, Asahikawa Medical University Hospital, Asahikawa, Hokkaido, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Torimoto
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004727:Endothelium / Q000166:cytology / Q000378:metabolism*; D019190:Iron Overload / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D016133:Polymerase Chain Reaction
chemical_list: D017077:Culture Media, Conditioned; D020932:Nerve Growth Factor
keywords: Defenestration; Iron; Liver sinusoidal endothelial cells; NGF