Upregulation of Hemoglobin Expression by Oxidative Stress in Hepatocytes and Its Implication in Nonalcoholic Steatohepatitis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Sep 21

PMID 21931690

Citations 69

Authors

Wensheng Liu

Susan S Baker

Robert D Baker

Norma J Nowak

Lixin Zhu

Affiliations

Soon will be listed here.

Abstract

Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was designed to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. Analysis of microarray gene expression data revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopsies from NASH patients. Increased hemoglobin expression in NASH was validated by quantitative real time PCR. However, the expression of hematopoietic transcriptional factors and erythrocyte specific marker genes were not increased, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, increased HBA1 and HBB expression in HepG2 and HEK293 cells. Importantly, hemoglobin overexpression suppressed oxidative stress in HepG2 cells. We concluded that hemoglobin is expressed by hepatocytes and oxidative stress upregulates its expression. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage in NASH.

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References

Tiniakos D, Vos M, Brunt E . Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010; 5:145-71. DOI: 10.1146/annurev-pathol-121808-102132. View

Mantena S, King A, Andringa K, Eccleston H, Bailey S . Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 2008; 44(7):1259-72. PMC: 2323912. DOI: 10.1016/j.freeradbiomed.2007.12.029. View

Grek C, Newton D, Spyropoulos D, Baatz J . Hypoxia up-regulates expression of hemoglobin in alveolar epithelial cells. Am J Respir Cell Mol Biol. 2010; 44(4):439-47. PMC: 3095918. DOI: 10.1165/rcmb.2009-0307OC. View

Richter F, Meurers B, Zhu C, Medvedeva V, Chesselet M . Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol. 2009; 515(5):538-47. PMC: 3123135. DOI: 10.1002/cne.22062. View

Stamatoyannopoulos G . Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005; 33(3):259-71. PMC: 2819985. DOI: 10.1016/j.exphem.2004.11.007. View

Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I, Son D . Hemoglobin is expressed by mesangial cells and reduces oxidant stress. J Am Soc Nephrol. 2008; 19(8):1500-8. PMC: 2488266. DOI: 10.1681/ASN.2007101085. View

Koury M, Sawyer S, Brandt S . New insights into erythropoiesis. Curr Opin Hematol. 2002; 9(2):93-100. DOI: 10.1097/00062752-200203000-00002. View

Kojima H, Sakurai S, Yoshiji H, Uemura M, Yoshikawa M, Fukui H . The role of radixin in altered localization of canalicular conjugate export pump Mrp2 in cholestatic rat liver. Hepatol Res. 2007; 38(2):202-10. DOI: 10.1111/j.1872-034X.2007.00209.x. View

Liu L, Zeng M, Stamler J . Hemoglobin induction in mouse macrophages. Proc Natl Acad Sci U S A. 1999; 96(12):6643-7. PMC: 21968. DOI: 10.1073/pnas.96.12.6643. View

10.

Schechter A . Hemoglobin research and the origins of molecular medicine. Blood. 2008; 112(10):3927-38. PMC: 2581994. DOI: 10.1182/blood-2008-04-078188. View

11.

Larter C, Chitturi S, Heydet D, Farrell G . A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010; 25(4):672-90. DOI: 10.1111/j.1440-1746.2010.06253.x. View

12.

Trak-Smayra V, Dargere D, Noun R, Albuquerque M, Yaghi C, Gannage-Yared M . Serum proteomic profiling of obese patients: correlation with liver pathology and evolution after bariatric surgery. Gut. 2008; 58(6):825-32. DOI: 10.1136/gut.2007.140087. View

13.

Zhu L, Baker S, Liu W, Tao M, Patel R, Nowak N . Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism. 2010; 60(7):1001-11. DOI: 10.1016/j.metabol.2010.10.003. View

14.

Leclercq I . Antioxidant defence mechanisms: new players in the pathogenesis of non-alcoholic steatohepatitis?. Clin Sci (Lond). 2003; 106(3):235-7. DOI: 10.1042/CS20030368. View

15.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View

16.

Schwimmer J, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork N . Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005; 42(3):641-9. DOI: 10.1002/hep.20842. View

17.

Kaser S, Ebenbichler C, Tilg H . Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease. Int J Clin Pract. 2010; 64(7):968-83. DOI: 10.1111/j.1742-1241.2009.02327.x. View

18.

Ohneda K, Yamamoto M . Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage. Acta Haematol. 2002; 108(4):237-45. DOI: 10.1159/000065660. View

19.

Tsutsui M, Tanaka N, Kawakubo M, Sheena Y, Horiuchi A, Komatsu M . Serum fragmented cytokeratin 18 levels reflect the histologic activity score of nonalcoholic fatty liver disease more accurately than serum alanine aminotransferase levels. J Clin Gastroenterol. 2010; 44(6):440-7. DOI: 10.1097/MCG.0b013e3181bdefe2. View

20.

Dowman J, Tomlinson J, Newsome P . Pathogenesis of non-alcoholic fatty liver disease. QJM. 2009; 103(2):71-83. PMC: 2810391. DOI: 10.1093/qjmed/hcp158. View