Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2017; 23(41): 7347-7358
Published online Nov 7, 2017. doi: 10.3748/wjg.v23.i41.7347
Reabsorption of iron into acutely damaged rat liver: A role for ferritins
Ihtzaz Ahmed Malik, Jörg Wilting, Giuliano Ramadori, Naila Naz
Ihtzaz Ahmed Malik, Jörg Wilting, Institute of Anatomy and Cell Biology, University Medical Center, D-37075 Goettingen, Germany
Giuliano Ramadori, Department of Gastroenterology and Endocrinology, University Medical Center, D-37075 Goettingen, Germany
Naila Naz, Faculty of Life Sciences, The University of Manchester, Manchester M13 9PL, United Kingdom
Author contributions: Malik IA, Ramadori G and Naz N designed the study; Malik IA and Naz N performed the experiments; Malik IA, Ramadori G and Naz N analyzed the data and wrote manuscript; Wilting J assisted to interpret the data and improved the manuscript; Ramadori G and Naz N contributed equally to this work.
Supported by the German Research Foundation, and the Open Access Publication Funds of the Göttingen University.
Institutional review board statement: The studies were performed according to the guidelines of good scientific practice.
Institutional animal care and use committee statement: The animal studies were reviewed and approved by the committee of the Central Institute for Animal Experiments of the University of Goettingen, and the Lower Saxony State Office for Consumer Protection and Food Safety (Study No. 33.9-42502-04-13/1086).
Conflict-of-interest statement: The authors declare that no actual or potential conflict-of-interest in relation to this article exists.
Data sharing statement: The data were obtained, analyzed and used by the authors only.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ihtzaz Ahmed Malik, PhD, Institute of Anatomy and Cell Biology, University Medical Center Goettingen, Kreuzbergring 36, D-37075 Goettingen, Germany. i.malik@med.uni-goettingen.de
Telephone: +49-551-398982 Fax: +49-551-397067
Received: July 16, 2017
Peer-review started: July 21, 2017
First decision: August 10, 2017
Revised: August 22, 2017
Accepted: September 13, 2017
Article in press: September 13, 2017
Published online: November 7, 2017
Processing time: 107 Days and 16.1 Hours
Abstract
AIM

To studied iron metabolism in liver, spleen, and serum after acute liver-damage, in relation to surrogate markers for liver-damage and repair.

METHODS

Rats received intraperitoneal injection of the hepatotoxin thioacetamide (TAA), and were sacrificed regularly between 1 and 96 h thereafter. Serum levels of transaminases and iron were measured using conventional laboratory assays. Liver tissue was used for conventional histology, immunohistology, and iron staining. The expression of acute-phase cytokines, ferritin light chain (FTL), and ferritin heavy chain (FTH) was investigated in the liver by qRT-PCR. Western blotting was used to investigate FTL and FTH in liver tissue and serum. Liver and spleen tissue was also used to determine iron concentrations.

RESULTS

After a short initial decrease, iron serum concentrations increased in parallel with serum transaminase (aspartate aminotransferase and alanine aminotransferase) levels, which reached a maximum at 48 h, and decreased thereafter. Similarly, after 48 h a significant increase in FTL, and after 72h in FTH was detected in serum. While earliest morphological signs of inflammation in liver were visible after 6 h, increased expression of the two acute-phase cytokines IFN-γ (1h) and IL-1β (3h) was detectable earlier, with maximum values after 12-24 h. Iron concentrations in liver tissue increased steadily between 1 h and 48 h, and remained high at 96 h. In contrast, spleen iron concentrations remained unchanged until 48 h, and increased mildly thereafter (96 h). Although tissue iron staining was negative, hepatic FTL and FTH protein levels were strongly elevated. Our results reveal effects on hepatic iron concentrations after direct liver injury by TAA. The increase of liver iron concentrations may be due to the uptake of a significant proportion of the metal by healthy hepatocytes, and only to a minor extent by macrophages, as spleen iron concentrations do not increase in parallel. The temporary increase of iron, FTH and transaminases in serum is obviously due to their release by damaged hepatocytes.

CONCLUSION

Increased liver iron levels may be the consequence of hepatocyte damage. Iron released into serum by damaged hepatocytes is obviously transported back and stored via ferritins.

Keywords: Iron metabolism; Ferritin; Liver; Cytokines; Acute liver damage

Core tip: In humans, an increase in hepatic iron concentration is caused by chronic hepatitis-C infection, alcohol abuse, and non-alcoholic fatty liver disease. The pathophysiology behind increased liver iron concentrations caused by acute liver damage has remained obscure. Using thioacetamide-injection in rats, we demonstrate that the increase in liver iron may be a consequence rather than the cause of hepatocyte damage. Thereby, iron is released into serum by damaged hepatocytes during acute liver damage, and reabsorbed by remaining hepatocytes (but not spleen) by means of ferritin L and ferritin H subunits. Our studies also show that ferritin H is a promising surrogate marker for damaged hepatocytes.