N-Acetylglucosaminyltransferase V regulates TGF-β response in hepatic stellate cells and the progression of steatohepatitis
N-Acetylglucosaminyltransferase V regulates TGF-β response in hepatic stellate cells and the progression of steatohepatitis
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DOI：
10.1093/glycob/cws012
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发表时间：
2012-06-01
期刊：
影响因子：
4.3
通讯作者：
Miyoshi, Eiji
中科院分区：
文献类型：
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作者：
Kamada, Yoshihiro;Mori, Kanako;Miyoshi, Eiji
n -乙酰氨基葡萄糖转移酶（N-Acetylglucosaminyltransferase V, GnT-V）是参与肿瘤转移和癌变的最重要的糖基转移酶之一，可催化天冬酰胺连接寡糖的β 1-6分支。虽然GnT-V的表达在慢性肝脏疾病中被诱导，但GnT-V在这些疾病中的生物学意义尚不清楚。本研究的目的是研究GnT-V对慢性肝炎进展的影响，采用GnT-V转基因（Tg）小鼠喂养高脂高胆固醇（HFHC）饮食，作为小鼠脂肪性肝炎的实验模型。虽然在野生型（WT）小鼠中观察到HFHC饮食增强了肝淋巴细胞浸润和纤维化，但在Tg小鼠中却明显阻止了这一现象。此外，Tg小鼠肝脏炎性Th1细胞因子基因表达明显低于WT小鼠。肝纤维化的抑制是由于肝星状细胞（HSCs）功能障碍所致，肝星状细胞通过产生转化生长因子(TGF)- β 1在肝纤维化中起关键作用。虽然tgf - β 1信号在Tg小鼠来源的hsc中与WT小鼠来源的hsc （WT- hsc）相比增强，但Tg小鼠来源的hsc中胶原表达显著降低。DNA芯片检测结果显示，tgf - β 1负反馈信号环氧化酶-2 （COX2）在tg - hsc中的表达明显高于wt - hsc。在tg - hsc中，COX2的产物前列腺素E2 （PGE2）的产生也显著升高。塞来昔布抑制COX2可降低tg - hsc中PGE2的表达，增加胶原蛋白的表达。总之，GnT-V通过调节淋巴细胞和HSC功能来阻止脂肪性肝炎的进展。
N-Acetylglucosaminyltransferase V (GnT-V), catalyzing beta 1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in tumor metastasis and carcinogenesis. Although the expression of GnT-V is induced in chronic liver diseases, the biological meaning of GnT-V in the diseases remains unknown. The aim of this study was to investigate the effects of GnT-V on the progression of chronic hepatitis, using GnT-V transgenic (Tg) mice fed a high fat and high cholesterol (HFHC) diet, an experimental model of murine steatohepatitis. Although enhanced hepatic lymphocytes infiltration and fibrosis were observed in wild-type (WT) mice fed the HFHC diet, they were dramatically prevented in Tg mice. In addition, the gene expression of inflammatory Th1 cytokines in the liver was significantly decreased in Tg mice than WT mice. Inhibition of liver fibrosis was due to the dysfunction of hepatic stellate cells (HSCs), which play pivotal roles in liver fibrosis through the production of transforming growth factor (TGF)-beta 1. Although TGF-beta 1 signaling was enhanced in Tg mouse-derived HSCs (Tg-HSCs) compared with WT mouse-derived HSCs (WT-HSCs), collagen expression was significantly reduced in Tg-HSCs. As a result from DNA microarray, cyclooxygenase-2 (COX2) expression, known as a negative feedback signal for TGF-beta 1, was significantly elevated in Tg-HSCs compared with WT-HSCs. Prostaglandin E2 (PGE2), the product of COX2, production was also significantly elevated in Tg-HSCs. COX2 inhibition by celecoxib decreased PGE2 and increased collagen expression in Tg-HSCs. In conclusion, GnT-V prevented steatohepatitis progression through modulating lymphocyte and HSC functions.