title: Inflammatory regulation of iron metabolism during thioacetamide-induced acute liver injury in rats.
abstract: Systemic iron homeostasis is tightly regulated by the interaction between iron regulatory molecules, mainly produced by the liver. However, the molecular mechanisms of iron regulation in liver diseases remain to be elucidated. Here we analyzed the expression profiles of iron regulatory molecules during transient iron overload in a rat model of thioacetamide (TAA)-induced acute liver injury. After TAA treatment, mild hepatocellular degeneration and extensive necrosis were observed in the centrilobular region at hour 10 and on day 1, respectively. Serum iron increased transiently at hour 10 and on day 1, in contrast to hypoferremia in other rodent models of acute inflammation reported previously. Thereafter, up-regulation of hepcidin, a central regulator of systemic iron homeostasis, was observed in hepatocytes on day 2. Expression of transferrin receptor 1 and ferritin subunits increased to a peak on day 3, followed by increases in liver iron content and stainable iron on day 5, in parallel with regeneration of hepatocytes. Histopathological lesions and hepatocellular iron accumulation disappeared until day 10. The hepcidin induction was preceded by activation of IL6/STAT3 pathway, whereas other pathways known to induce hepcidin were down-regulated. IL6 was expressed by MHC class II-positive macrophages in the portal area, suggestive of dendritic cells. Our results suggest that IL6 released by portal macrophages may regulate hepatocyte hepcidin expression via STAT3 activation during transient iron overload in TAA-induced acute liver injury.
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan. Electronic address: izawa@vet.osakafu-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan.
authors.forename: Kavindra Kumara
authors.initials: KK
authors.lastname: Wijesundera
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan.
authors.forename: Hossain M
authors.initials: HM
authors.lastname: Golbar
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Japan.
authors.forename: Jyoji
authors.initials: J
authors.lastname: Yamate
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D013853:Thioacetamide / Q000633:toxicity*
chemical_list: D035925:Iron-Regulatory Proteins; D013853:Thioacetamide; D007501:Iron
keywords: Acute liver injury; Hepcidin; Inflammation; Iron regulation; Macrophage