Brief Articles
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World J Gastroenterol. Sep 28, 2009; 15(36): 4499-4510
Published online Sep 28, 2009. doi: 10.3748/wjg.15.4499
Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells
Wei-Hong Hou, Lisa Rossi, Ying Shan, Jian-Yu Zheng, Richard W Lambrecht, Herbert L Bonkovsky
Wei-Hong Hou, Jian-Yu Zheng, The Cannon Research Center and the Liver, Digestive Disease, and Metabolism Laboratory, Carolinas Medical Center, Charlotte, NC, 28203, United States; The University of North Carolina, Charlotte, NC 28223, United States
Lisa Rossi, Richard W Lambrecht, Department of Medicin e, University of Connecticut Health Center, Farmington, CT 06030, United States
Ying Shan, Department of Molecular, Microbial & Structural Biology, University of Connecticut Health Center, Farmington, CT 06030, United States
Herbert L Bonkovsky, The Cannon Research Center and the Liver, Digestive Disease, and Metabolism Laboratory, Carolinas Medical Center, Charlotte, NC, 28203, United States; The University of North Carolina, Charlotte 28223, United States; The University of North Carolina, Chapel Hill, NC 27514, United States; Departments of Medicine, and Molecular, Microbial & Structural Biology, University of Connecticut Health Center, Farmington, CT 06030, United States; Department of Medicine of the University of Massachusetts Medical School, Worcester, MA 01655, United States
Author contributions: Hou WH, Shan Y and Rossi L each contributed to the conception, experimentation and drafting of this paper; Zheng JY performed experiments as well as contributing to the drafting of the paper; Lambrecht RW and Bonkovsky HL were instrumental in the conception of the project and the drafting of the paper.
Supported by Grant (DK RO1 38825) and contracts (DK NO1 29236 and UO1 DK 06193) from the National Institutes of Health (NIDDK)
Correspondence to: Herbert L Bonkovsky, MD, Cannon Research Center, Suite 201, Carolinas Medical Center, 1542 Garden Terrace, Charlotte, NC 28203, United States. herbert.bonkovsky@carolinashealthcare.org
Telephone: +1-704-3553959 Fax: +1-704-3557648
Received: May 26, 2009
Revised: September 2, 2009
Accepted: September 9, 2009
Published online: September 28, 2009
Abstract

AIM: To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins.

METHODS: Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots.

RESULTS: Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up-regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2-siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them.

CONCLUSION: Excess iron up-regulates HMOX1 and down-regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection.

Keywords: Deferoxamine; Core protein of hepatitis C virus; Hepatitis C; Iron; Heme oxygenase-1; Nuclear factor-erythroid 2-related factor 2; Bach1; Oxidative stress; Nonstructural 5A protein of hepatitis C virus