Title page for etd-0825109-033053


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URN etd-0825109-033053
Author Ying-hsien Kao
Author's Email Address danyhkao@gmail.com
Statistics This thesis had been viewed 5575 times. Download 1340 times.
Department Biological Sciences
Year 2008
Semester 2
Degree Ph.D.
Type of Document
Language English
Title Investigation on the Pathological Role of Hepatoma-Derived Growth Factor in Hepatic Fibrogenesis
Date of Defense 2008-07-07
Page Count 122
Keyword
  • hepatoma-derived growth factor
  • liver fibrosis
  • hepatocytes
  • transforming growth factor-beta
  • Abstract Liver fibrosis, a major medical problem with significant morbidity and
    mortality, is considered as a wound-healing response to a variety of chronic
    stimuli. It is characterized by an excessive deposition of extracellular
    matrix (ECM) proteins, which disrupts the normal architecture of liver and
    ultimately leads to pathophysiological damage to liver. Hepatoma-derived
    growth factor (HDGF), a growth factor originally purified from hepatoma
    cells, is highly expressed in fetal hepatocytes and hepatoma. It is known to
    play multifunctional roles in mitogenesis, organogenesis, embryogenesis,
    and tumorigenesis. Its expression correlates with the proliferating state of
    hepatocellular carcinoma (HCC) and serves as a prognostic factor. Since
    liver fibrosis frequently occurs prior to HCC development, the specific aim
    of this study is to investigate the role of HDGF in the progression of liver
    fibrosis by using animal models of mice receiving either bile duct ligation
    surgery or carbon tetrachloride administration. Quantitative real-time PCR
    and Western blotting analysis showed a significant elevation of HDGF
    expression in both models. HDGF levels correlated with progression of
    liver fibrosis in a time-dependent manner as well as paralleled with the
    expression of other two fibrotic markers, transforming growth factor-b1
    (TGF-b1) and pro-collagen type I, in fibrotic livers. Intriguingly, the
    over-expressed HDGF protein was localized mainly in perivenous
    hepatocytes of fibrotic livers. Besides, adenovirus-mediated HDGF gene
    delivery potentiated the production of TGF-b1 and pro-collagen type I,
    thereby enhancing the intrahepatic collagen matrix deposits as evidenced
    by Sirius red stain and morphometrical analysis. In cultured hepatocytes,
    TGF-b1 and HDGF mutually up-regulated their de novo synthesis only
    when grown on collagen-coated matrix, strongly suggesting that the
    TGF-b1- and/or HDGF-driven pro-fibrogenic signaling is
    collagen-dependent and a vicious circle may exist at the initial stage of
    hepatic fibrogenesis. Moreover, administration with recombinant HDGF
    stimulated BrdU uptake and synthesis of both a-smooth muscle actin and
    pro-collagen type I in cultured hepatic stellate cells, implicating that a
    mode of paracrinal action lies between these two cell types. In conclusion,
    HDGF plays a pro-fibrogenic role during liver fibrosis and blockade of
    HDGF pathway may potentially constitute the preventive or therapeutic
    strategies for chronic liver diseases.
    Advisory Committee
  • Hung-tu Huang - chair
  • Tsung-hui Hu - co-chair
  • Jiin-haur Chuang - co-chair
  • Ming-hong Tai - advisor
  • David Chao - advisor
  • Files
  • etd-0825109-033053.pdf
  • indicate access worldwide
    Date of Submission 2009-08-25

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