Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 8, 2016; 8(4): 211-225
Published online Feb 8, 2016. doi: 10.4254/wjh.v8.i4.211
Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver
Sizhao Lu, Robert G Bennett, Kusum K Kharbanda, Duygu Dee Harrison-Findik
Sizhao Lu, Robert G Bennett, Department of Biochemistry, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
Robert G Bennett, Division of Endocrinology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-4130, United States
Robert G Bennett, Kusum K Kharbanda, Nebraska-Western Iowa VA Health Care System, Omaha, NE 68105, United States
Kusum K Kharbanda, Duygu Dee Harrison-Findik, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-2000, United States
Author contributions: Lu S contributed to study design, data acquisition and drafting of the manuscript; Harrison-Findik DD obtained funding, contributed to study concept and supervision, and critical revision of the manuscript; Bennett RG and Kharbanda K helped with technical support and critical reading of the manuscript.
Supported by NIH grant No. R01AA017738 (to Harrison-Findik DD); and University of Nebraska Medical Center Graduate Assistantship/Fellowship (to Lu S).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of University of Nebraska Medical Center (IACUC protocol No. 03-075-10-FC).
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
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:
Correspondence to: Duygu Dee Harrison-Findik, DVM, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, 92000 UNMC, Omaha, NE 68198-2000, United States.
Telephone: +1-402-5596209 Fax: +1-402-5599004
Received: August 2, 2015
Peer-review started: August 3, 2015
First decision: September 29, 2015
Revised: October 14, 2015
Accepted: November 13, 2015
Article in press: November 13, 2015
Published online: February 8, 2016

AIM: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD).

METHODS: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction.

RESULTS: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes.

CONCLUSION: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.

Keywords: Hamp, Iron, Non-alcoholic steatohepatitis, Metabolic genes, Steatosis, Non-alcoholic fatty liver disease, Steatohepatitis

Core tip: Due to obesity epidemic the incidence of non-alcoholic fatty liver disease (NAFLD) is on the rise. Iron contributes to disease severity and the expression of key iron regulatory hormone, hepcidin is modulated in NAFLD patients. The underlying mechanisms are unknown. We have generated hepcidin knockout mice with iron overload phenotype. This study investigates the role of hepcidin in NAFLD by using high fat and high sucrose-fed knockout mice as an experimental model of NAFLD. Our findings showed attenuated steatosis and early fibrosis development suggesting a role for hepcidin in the regulation of metabolic processes in the liver, and in NAFLD.