Pituitary tumor transforming gene as a novel regulatory factor of liver fibrosis.
OBJECTIVE
Pituitary tumor-transforming gene (PTTG) is involved in multiple cellular pathways. We studied the development of liver fibrosis induced by thioacetamide (TAA) in knockout (PTTG-/-) and wildtype (PTTG+/+) mice.


METHODS
Liver fibrosis in PTTG+/+ and PTTG-/- mice was induced by escalating dose TAA treatment (50-400mg/kg, i.p.) for 12 weeks and assessed by histochemistry, immunohistochemistry, liver hydroxyproline, serum fibrosis markers and fibrosis-related mRNA expression by real-time PCR determination.


RESULTS
Both PTTG+/+ and PTTG-/- mice treated with TAA developed signs of fibrosis and inflammatory cell infiltration. However, histological signs of bridging fibrosis and connective tissue square morphometry were significantly attenuated in mice lacking PTTG. α-SMA immunohistochemistry revealed that hepatic stellate cell activation was markedly reduced in PTTG-/- mice compared to wildtype controls. Hepatic hydroxyproline levels were significantly lower in fibrotic PTTG-/- group. The serum TNFα and hepatic TNFα mRNA expression were significantly lower in fibrotic PTTG-/- animals, as well as hepatic TGFβ and VEGF mRNA levels compared to TAA-treated wildtype controls. Serum hyaluronate and TGFβ levels were markedly elevated in fibrotic mice of both genotypes, but were not altered by the absence of PTTG.


CONCLUSIONS
TAA-induced fibrosis development is significantly ameliorated in PTTG-/- mice. These animals demonstrated diminished stellate cell activation, suppressed circulating serum markers of inflammation, fibrogenesis and angiogenesis. The presented findings suggest that PTTG is functionally required for hepatic fibrosis progression in an animal model of chronic liver injury. PTTG can be considered as a new important target for prevention and treatment of liver fibrosis/cirrhosis.
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus; School of Medical Sciences, Bialystok, Poland. Electronic address: buko@bioch.basnet.by.
Vyacheslav
V
Buko
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus.
Elena
E
Belonovskaya
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus.
Elena
E
Naruta
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus.
Oxana
O
Lukivskaya
Lviv National Ivan Franko University, Lviv, Ukraine.
Olena
O
Kanyuka
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus.
Olga
O
Zhuk
School of Medical Sciences, Bialystok, Poland.
Robert
R
Kranc
Lviv National Ivan Franko University, Lviv, Ukraine; Institute of Cell Biology, National Academy of Sciences, Lviv, Ukraine.
Rostislav
R
Stoika
Lviv National Ivan Franko University, Lviv, Ukraine.
Natalia
N
Sybirna
D000818:Animals; D015415:Biomarkers / Q000097:blood; D005809:Genes, Regulator / Q000235:genetics*; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D064249:Securin / Q000235:genetics / Q000378:metabolism*; D013853:Thioacetamide / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D015415:Biomarkers; D064249:Securin; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D006909:Hydroxyproline
Angiogenesis; Fibrogenesis; Inflammation; Liver fibrosis; Pituitary tumor transforming factor; Thioacetamide