title: Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis.
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.
authors.affiliation: Digestive Diseases and Nutrition Center, Department of Pediatrics, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Susan S
authors.initials: SS
authors.lastname: Baker
authors.forename: Robert D
authors.initials: RD
authors.lastname: Baker
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Nowak
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005260:Female; D006442:Glycated Hemoglobin / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006454:Hemoglobins / Q000235:genetics* / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D055815:Young Adult; D055542:alpha-Globins / Q000235:genetics* / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006442:Glycated Hemoglobin; D006454:Hemoglobins; D055542:alpha-Globins; D055544:beta-Globins