Intrahepatic gene expression profiles and alpha-smooth muscle actin patterns in hepatitis C virus induced fibrosis

Daryl T Y Lau, Bruce A. Luxon, Shu Yuan Xiao, Michael R. Beard, Stanley M. Lemon

    Research output: Contribution to journalArticle

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    Abstract

    To gain insight into pathogenic mechanisms underlying fibrosis in hepatitis C virus (HCV)-mediated liver injury, we compared intrahepatic gene expression profiles in HCV-infected patients at different stages of fibrosis and α-smooth muscle actin (α-SMA) staining patterns. We studied 21 liver biopsy specimens: 5 had no fibrosis (Ludwig-Batts stage 0); 10 had early portal or periportal fibrosis (stages 1 and 2); and 6, advanced fibrosis (stages 3 and 4). None of the patients had hepatocellular carcinoma. Transcriptional profiles were determined by high-density oligonucleotide microarrays. ANOVA identified 157 genes for which transcript abundance was associated with fibrosis stage. These defined three distinct hierarchical clusters of patients. Patients with predominantly stage 0 fibrosis had increased abundance of mRNAs linked to glycolipid metabolism. PDGF, a potent stellate cell mitogen, was also increased. Transcripts with increased abundance in stages 1 and 2 fibrosis were associated with oxidative stress, apoptosis, inflammation, proliferation, and matrix degradation, whereas transcripts increased in stages 3 and 4 were associated with fibrogenesis and cellular proliferation. Cells staining for α-SMA were detectable at all stages but infrequent in advanced fibrosis without active inflammation. A high frequency of such cells was associated with mRNAs linked to glycolipid metabolism. In conclusion, the presence of α-SMA-positive HSCs and expression of PDGF in stage O fibrosis suggests that stellate cells are activated early in HCV-mediated injury, possibly in response to oxidative stress resulting from inflammation and lipid metabolism. Increased abundance of transcripts linked to cellular proliferation in advanced fibrosis is consistent with a predisposition to cancer.

    Original languageEnglish (US)
    Pages (from-to)273-281
    Number of pages9
    JournalHepatology
    Volume42
    Issue number2
    DOIs
    StatePublished - Aug 2005

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    Transcriptome
    Hepacivirus
    Smooth Muscle
    Actins
    Fibrosis
    Glycolipids
    Inflammation
    Oxidative Stress
    Cell Proliferation
    Staining and Labeling
    Messenger RNA
    Liver
    Wounds and Injuries
    Oligonucleotide Array Sequence Analysis
    Mitogens
    Lipid Metabolism
    Hepatocellular Carcinoma
    Analysis of Variance
    Apoptosis
    Biopsy

    ASJC Scopus subject areas

    • Hepatology

    Cite this

    Intrahepatic gene expression profiles and alpha-smooth muscle actin patterns in hepatitis C virus induced fibrosis. / Lau, Daryl T Y; Luxon, Bruce A.; Xiao, Shu Yuan; Beard, Michael R.; Lemon, Stanley M.

    In: Hepatology, Vol. 42, No. 2, 08.2005, p. 273-281.

    Research output: Contribution to journalArticle

    Lau, Daryl T Y ; Luxon, Bruce A. ; Xiao, Shu Yuan ; Beard, Michael R. ; Lemon, Stanley M. / Intrahepatic gene expression profiles and alpha-smooth muscle actin patterns in hepatitis C virus induced fibrosis. In: Hepatology. 2005 ; Vol. 42, No. 2. pp. 273-281.
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    abstract = "To gain insight into pathogenic mechanisms underlying fibrosis in hepatitis C virus (HCV)-mediated liver injury, we compared intrahepatic gene expression profiles in HCV-infected patients at different stages of fibrosis and α-smooth muscle actin (α-SMA) staining patterns. We studied 21 liver biopsy specimens: 5 had no fibrosis (Ludwig-Batts stage 0); 10 had early portal or periportal fibrosis (stages 1 and 2); and 6, advanced fibrosis (stages 3 and 4). None of the patients had hepatocellular carcinoma. Transcriptional profiles were determined by high-density oligonucleotide microarrays. ANOVA identified 157 genes for which transcript abundance was associated with fibrosis stage. These defined three distinct hierarchical clusters of patients. Patients with predominantly stage 0 fibrosis had increased abundance of mRNAs linked to glycolipid metabolism. PDGF, a potent stellate cell mitogen, was also increased. Transcripts with increased abundance in stages 1 and 2 fibrosis were associated with oxidative stress, apoptosis, inflammation, proliferation, and matrix degradation, whereas transcripts increased in stages 3 and 4 were associated with fibrogenesis and cellular proliferation. Cells staining for α-SMA were detectable at all stages but infrequent in advanced fibrosis without active inflammation. A high frequency of such cells was associated with mRNAs linked to glycolipid metabolism. In conclusion, the presence of α-SMA-positive HSCs and expression of PDGF in stage O fibrosis suggests that stellate cells are activated early in HCV-mediated injury, possibly in response to oxidative stress resulting from inflammation and lipid metabolism. Increased abundance of transcripts linked to cellular proliferation in advanced fibrosis is consistent with a predisposition to cancer.",
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