Buko Vyacheslav, Belonovskaya Elena, Naruta Elena, Lukivskaya Oxana, Kanyuka Olena, Zhuk Olga, Kranc Robert, Stoika Rostislav, Sybirna Natalia
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus; School of Medical Sciences, Bialystok, Poland.
Institute of Biochemistry of Biologically Active Compounds, National Academy of Sciences, Grodno, Belarus.
Life Sci. 2015 Jul 1;132:34-40. doi: 10.1016/j.lfs.2015.04.010. Epub 2015 Apr 29.
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.
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.
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.
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.
垂体肿瘤转化基因（PTTG）参与多种细胞信号通路。我们研究了硫代乙酰胺（TAA）诱导的基因敲除（PTTG-/-）和野生型（PTTG+/+）小鼠肝纤维化的发展情况。
通过递增剂量的TAA处理（50-400mg/kg，腹腔注射）12周诱导PTTG+/+和PTTG-/-小鼠发生肝纤维化，并通过组织化学、免疫组织化学、肝脏羟脯氨酸、血清纤维化标志物以及实时PCR测定纤维化相关mRNA表达进行评估。
用TAA处理的PTTG+/+和PTTG-/-小鼠均出现纤维化和炎性细胞浸润迹象。然而，在缺乏PTTG的小鼠中，桥接纤维化和结缔组织方形形态测量的组织学迹象明显减轻。α-SMA免疫组织化学显示，与野生型对照相比，PTTG-/-小鼠肝星状细胞活化明显减少。纤维化的PTTG-/-组肝脏羟脯氨酸水平显著降低。与TAA处理的野生型对照相比，纤维化的PTTG-/-动物血清TNFα和肝脏TNFα mRNA表达显著降低，肝脏TGFβ和VEGF mRNA水平也显著降低。两种基因型的纤维化小鼠血清透明质酸和TGFβ水平均显著升高，但不受PTTG缺失的影响。
PTTG-/-小鼠中TAA诱导的纤维化发展明显改善。这些动物表现出星状细胞活化减少，循环血清炎症、纤维生成和血管生成标志物受到抑制。研究结果表明，在慢性肝损伤动物模型中，PTTG对肝纤维化进展具有功能性作用。PTTG可被视为预防和治疗肝纤维化/肝硬化的新的重要靶点。
