| 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. |
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