title: Iron overload in hereditary tyrosinemia type 1 induces liver injury through the Sp1/Tfr2/hepcidin axis.
abstract: Iron is an essential metal for fundamental metabolic processes, but little is known regarding the involvement of iron in other nutritional disorders. In the present study, we investigated disordered iron metabolism in a murine model of hereditary tyrosinemia type I (HT1), a disease of the tyrosine degradation pathway.
  
  
  
  We analysed the status of iron accumulation following NTBC withdrawal from Fah(-/-) mice, a murine model for HT1. Liver histology and serum parameters were used to assess the extent of liver injury and iron deposition. To determine the physiological significance of iron accumulation, mice were subjected to a low-iron food intake to reduce the iron accumulation. Mechanistic studies were performed on tissues and cells using immunoblotting, qRT-PCR, adenovirus transfection and other assays.
  
  
  
  Severe iron overload was observed in the murine model of HT1 with dramatically elevated hepatic and serum iron levels. Mechanistic studies revealed that downregulation and dysfunction of Tfr2 decreased hepcidin, leading to iron overload. The Fah(-/-) hepatocytes lost the ability of transferrin-sensitive induction of hepcidin. Forced expression of Tfr2 in the murine liver reduced the iron accumulation. Moreover, transcription factor Sp1 was downregulated and identified as a new regulator of Tfr2 here. Additionally, low-iron food intake effectively reduced the iron deposits, protected the liver and prolonged the survival in these mice.
  
  
  
  Iron was severely overloaded in the HT1 mice via the Sp1/Tfr2/Hepcidin axis. The iron overload induced liver injury in the HT1 mice, and reduction of the iron accumulation ameliorated liver injury.
  
  
  
  Primary and secondary iron overload is an abnormal status affecting millions of people worldwide. Here, we reported severe iron overload in a murine model of HT1, a disease of the tyrosine degradation pathway, and elucidated the mechanistic basis and the physiological significance of iron overload in HT1. These studies are of general interest not only with respect to secondary iron-induced liver injury in HT1 but also are important to elucidate the crosstalk between the two metabolic pathways.
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Wen-Dai
authors.initials: WD
authors.lastname: Bao
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yue-Zhen
authors.initials: YZ
authors.lastname: Deng
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Ling-Yun
authors.initials: LY
authors.lastname: Long
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Dong-Xian
authors.initials: DX
authors.lastname: Guan
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Qian
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Peng
authors.initials: P
authors.lastname: An
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Feng
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: He
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, 12-01, Singapore 117599, Singapore; Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA 90048, USA.
authors.forename: H
authors.initials: H
authors.lastname: Phillip Koeffler
authors.affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.
authors.forename: Ronggui
authors.initials: R
authors.lastname: Hu
authors.affiliation: Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, 399 Wanyuan Road, Minhang District, Shanghai 201102, PR China.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, MN 55455, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Nutrition, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Institute of Nutrition Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China. Electronic address: dxie@sibs.ac.cn.
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
mesh_terms: D000818:Animals; D064451:Hepcidins; D007501:Iron; D019190:Iron Overload; D008099:Liver / Q000293:injuries*; D051379:Mice; D020176:Tyrosinemias
chemical_list: D064451:Hepcidins; D007501:Iron
keywords: Hereditary tyrosinemia; Iron overload; Liver injury; Low-iron food; Tfr2/Hepcidin