An Altered Pattern of Liver Apolipoprotein A-I Isoforms Is Implicated in Male Chronic Hepatitis B Progression

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Technical Note

An Altered Pattern of Liver Apolipoprotein A-I Isoforms Is Implicated in Male

Chronic Hepatitis B Progression

Fu Yang†, Yixuan Yin†, Fang Wang*, Ling Zhang, Yuqi Wang and Shuhan Sun*

Department of Medical Genetics, Second Military Medical University, Shanghai,

China

J. Proteome Res., Article ASAP

DOI: 10.1021/pr900593r

Publication Date (Web): September 29, 2009

Copyright © 2009 American Chemical Society

* To whom correspondence should be addressed. Professor Shuhan Sun, e-mail,

shsun@...; Professor Fang Wang, e-mail, WFSJZ70@..., Department

of Medical Genetics, Second Military Medical University, 800 Xiangyin Road,

Shanghai 200433, P. R. China. Tel: +86-021-81871053. Fax: +86-021-81871053., †

Both authors contributed equally to the work.

Abstract

Chronic hepatitis B (CHB) appears to progress more rapidly in males than in

females, and CHB-related hepatic cirrhosis and hepatocellular carcinoma are

predominately diseases that tend to occur in men and postmenopausal women. To

obtain more insight into the underlying mechanisms of gender disparity of CHB

progress, two-dimensional difference gel electrophoresis was employed to compare

liver proteome of C57BL/6 and HBV transgenic (HBV-Tg) mice both in male and

female groups. We identified 8 differently expressed proteins in male HBV-Tg

mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be

down-regulated in male and female HBV-Tg mouse liver. It is more interesting

that the pattern of liver Apo A-I isoforms was altered in male HBV-Tg mice but

not in female HBV-Tg mice. Our further results indicated that the basic Apo A-I

isoform, based on pI positions from serum 2-dimensional Western blotting,

increased in male CHB patient sera but not in female CHB patient sera. Finally,

we identified that the oxidative modification Apo A-I mainly reside in basic

isoform. This pattern of selectively modified Apo A-I isoforms may be considered

as a pathological hallmark that may extend our knowledge of the molecular

pathogenesis of CHB progression.

Introduction

--------------------------------------------------------------------------------

Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma

(HCC).(1) One interesting feature of CHB-related HCC is the male

predominance,(2-4) with a male-to-female ratio of 5−7:1.(5) There is similar

or even more pronounced gender disparity in hepatitis B virus (HBV) transgenic

mouse models.(6, 7) All these facts indicate that HBV influences the function of

male and female host cells in different ways.

Many researchers focus on androgen and estrogen. Some researchers’ data

provide strong evidence for CHB-related HCC risk among men who have higher

levels of androgen signaling and increased androgen receptor-mediated

transcriptional activity.(8, 9) However, many other studies suggest that the

greater progression of hepatic fibrosis and HCC in males may be due to a lower

production of estradiol and a lessened response to the action of estradiol.(10,

11) Willscot E. Naugler and his colleagues think that estrogen-mediated

restraint of IL-6 production by Kupffer cells reduces the risk of chemically

induced liver carcinogenesis in females.(12)

In addition to host sex hormone levels, the virus itself may also affect the

course of this disease. Hepatitis B virus x protein (HBx), one of the important

antigens of HBV, likely augments androgen receptor activity by increasing the

phosphorylation of the androgen receptor, which provides an explanation for the

male predominance of HCC in HBV-infected individuals.(13) But in another study,

the authors suggest that hepatitis B virus surface antigen (HBsAg) may be the

major risk factor affecting the gender difference in the causes of HCC because

estrogen receptor-β was extremely up-regulated in tumor tissues of male HBsAg

transgenic mice. It seems likely that overexpression of estrogen receptor-β

could cause changes in the levels and in the expression of target genes that

affect genomic stability, eventually contributing to the development of HCC.(7)

Overall, the mechanisms that account for this gender disparity remain unclear.

We need some new points of view and methods to study this problem. Recently,

many researchers have conducted systematic-omics studies using proteomics,

transcriptomics, genomics and metabolomics to elucidate deregulated proteins,

mRNAs, genes and metabolites involved in the progression of CHB.(14-17) In this

study, we focused on 6−8-week-old male and female HBV-transgenic (HBV-Tg)

mouse liver, which represents the typical age at which early pathological

lesions are detectable.(17) Because of the great sensitivity and dynamic range

that are afforded by fluorescent tags Cy2, Cy3 and Cy5, two-dimensional

difference gel electrophoresis (2-D DIGE) can give much greater accuracy of

quantization.(18) To obtain more insight into the underlying mechanisms of the

gender disparity of CHB progression, 2-D DIGE was employed to compare the liver

proteome of C57BL/6 and HBV-Tg mice in males and females. Our objective here was

to systematically identify relevant biomarkers and to pinpoint pathways that are

differently affected by HBV transgene in male and female mice.

[Guest guest]

FULL TEXT:

http://pubs.acs.org/stoken/presspac/presspac/full/10.1021/pr900593r?cookieSet=1

ACS Publications

Technical Note

An Altered Pattern of Liver Apolipoprotein A-I Isoforms Is Implicated in Male

Chronic Hepatitis B Progression

Fu Yang†, Yixuan Yin†, Fang Wang*, Ling Zhang, Yuqi Wang and Shuhan Sun*

Department of Medical Genetics, Second Military Medical University, Shanghai,

China

J. Proteome Res., Article ASAP

DOI: 10.1021/pr900593r

Publication Date (Web): September 29, 2009

Copyright © 2009 American Chemical Society

* To whom correspondence should be addressed. Professor Shuhan Sun, e-mail,

shsun@...; Professor Fang Wang, e-mail, WFSJZ70@..., Department

of Medical Genetics, Second Military Medical University, 800 Xiangyin Road,

Shanghai 200433, P. R. China. Tel: +86-021-81871053. Fax: +86-021-81871053., †

Both authors contributed equally to the work.

Abstract

Chronic hepatitis B (CHB) appears to progress more rapidly in males than in

females, and CHB-related hepatic cirrhosis and hepatocellular carcinoma are

predominately diseases that tend to occur in men and postmenopausal women. To

obtain more insight into the underlying mechanisms of gender disparity of CHB

progress, two-dimensional difference gel electrophoresis was employed to compare

liver proteome of C57BL/6 and HBV transgenic (HBV-Tg) mice both in male and

female groups. We identified 8 differently expressed proteins in male HBV-Tg

mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be

down-regulated in male and female HBV-Tg mouse liver. It is more interesting

that the pattern of liver Apo A-I isoforms was altered in male HBV-Tg mice but

not in female HBV-Tg mice. Our further results indicated that the basic Apo A-I

isoform, based on pI positions from serum 2-dimensional Western blotting,

increased in male CHB patient sera but not in female CHB patient sera. Finally,

we identified that the oxidative modification Apo A-I mainly reside in basic

isoform. This pattern of selectively modified Apo A-I isoforms may be considered

as a pathological hallmark that may extend our knowledge of the molecular

pathogenesis of CHB progression.

Introduction

--------------------------------------------------------------------------------

Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma

(HCC).(1) One interesting feature of CHB-related HCC is the male

predominance,(2-4) with a male-to-female ratio of 5−7:1.(5) There is similar

or even more pronounced gender disparity in hepatitis B virus (HBV) transgenic

mouse models.(6, 7) All these facts indicate that HBV influences the function of

male and female host cells in different ways.

Many researchers focus on androgen and estrogen. Some researchers’ data

provide strong evidence for CHB-related HCC risk among men who have higher

levels of androgen signaling and increased androgen receptor-mediated

transcriptional activity.(8, 9) However, many other studies suggest that the

greater progression of hepatic fibrosis and HCC in males may be due to a lower

production of estradiol and a lessened response to the action of estradiol.(10,

11) Willscot E. Naugler and his colleagues think that estrogen-mediated

restraint of IL-6 production by Kupffer cells reduces the risk of chemically

induced liver carcinogenesis in females.(12)

In addition to host sex hormone levels, the virus itself may also affect the

course of this disease. Hepatitis B virus x protein (HBx), one of the important

antigens of HBV, likely augments androgen receptor activity by increasing the

phosphorylation of the androgen receptor, which provides an explanation for the

male predominance of HCC in HBV-infected individuals.(13) But in another study,

the authors suggest that hepatitis B virus surface antigen (HBsAg) may be the

major risk factor affecting the gender difference in the causes of HCC because

estrogen receptor-β was extremely up-regulated in tumor tissues of male HBsAg

transgenic mice. It seems likely that overexpression of estrogen receptor-β

could cause changes in the levels and in the expression of target genes that

affect genomic stability, eventually contributing to the development of HCC.(7)

Overall, the mechanisms that account for this gender disparity remain unclear.

We need some new points of view and methods to study this problem. Recently,

many researchers have conducted systematic-omics studies using proteomics,

transcriptomics, genomics and metabolomics to elucidate deregulated proteins,

mRNAs, genes and metabolites involved in the progression of CHB.(14-17) In this

study, we focused on 6−8-week-old male and female HBV-transgenic (HBV-Tg)

mouse liver, which represents the typical age at which early pathological

lesions are detectable.(17) Because of the great sensitivity and dynamic range

that are afforded by fluorescent tags Cy2, Cy3 and Cy5, two-dimensional

difference gel electrophoresis (2-D DIGE) can give much greater accuracy of

quantization.(18) To obtain more insight into the underlying mechanisms of the

gender disparity of CHB progression, 2-D DIGE was employed to compare the liver

proteome of C57BL/6 and HBV-Tg mice in males and females. Our objective here was

to systematically identify relevant biomarkers and to pinpoint pathways that are

differently affected by HBV transgene in male and female mice.