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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.

SUBMITTER: Liu W

PROVIDER: S-EPMC3171444 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis.

Liu Wensheng W Baker Susan S SS Baker Robert D RD Nowak Norma J NJ Zhu Lixin L

PloS one 20110912 9

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) ...[more]

PMID: 21931690

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Project description:Aldo-keto reductase 1B10 (AKR1B10), a member of aldo-keto reductase superfamily, contributes to detoxification of xenobiotics and metabolization of physiological substrates. Although increased expression of AKR1B10 was found in hepatocellular carcinoma (HCC), the role of AKR1B10 in the development of HCC remains unclear. This study aims to illustrate the role of AKR1B10 in hepatocarcinogenesis based on its intrinsic oxidoreduction abilities. HCC cell lines with AKR1B10 overexpression or knockdown were treated with doxorubicin or hydrogen peroxide to determinate the influence of aberrant AKR1B10 expression on cells' response to oxidative stress. Using Akr1b8 (the ortholog of human AKR1B10) knockout mice, diethylnitrosamine (DEN) induced liver injury, chronic inflammation and hepatocarcinogenesis were explored. Clinically, the pattern of serum AKR1B10 relevant to disease progression was investigated in a patient cohort with chronic hepatitis B (n=30), liver cirrhosis (n=30) and HCC (n=40). AKR1B10 expression in HCC tissues was analyzed using both the TCGA database (n=371) and our collected HCC samples (n=67). AKR1B10 overexpression reduced hepatocyte injury while AKR1B10 knockdown augmented reactive oxygen species (ROS) accumulation and apoptotic cell death. Consistently, Akr1b8 deficiency in mice promoted DEN-induced hepatocyte damage and liver inflammation characterized by increased phospho-H2AX, serum alanine aminotransferase, interleukin-6 and tumor necrosis factor alpha level, myeloid cell infiltration and led to more severe hepatocarcinogenesis and metastasis compared with wild type mice due to significant alteration on detoxification and oxidoreduction. AKR1B10 was compensatory expressed and gradually upregulated in the process of liver disease progression in HCC and increased oxidative stress upregulated AKR1B10 through NRF2. Our results here suggested that through oxidoreduction and detoxification, AKR1B10 played an important role in protecting hepatocytes from damage induced by ROS. Deficiency of AKR1B10 might accelerate hepatotoxin and inflammation-associated hepatocarcinogenesis. AKR1B10 expression elevation in HCC could be a result of compensatory upregulation, rather than a driver of malignant transformation during the development of HCC.

Dataset Information

Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis.

Publications

Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis.

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