Prevention of Cell Growth by Suppression of Villin Expression in Lithocholic Acid-Stimulated HepG2 Cells
Prevention of Cell Growth by Suppression of Villin Expression in Lithocholic Acid-Stimulated HepG2 Cells
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DOI：
10.1369/0022155418804507
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发表时间：
2019-02-01
影响因子：
3.2
通讯作者：
Tamaki, Keiji
中科院分区：
文献类型：
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作者：
Ozeki, Munetaka;Aini, Wulamujiang;Tamaki, Keiji
胆汁淤积是一种胆汁流动中断的情况，石胆酸在引起严重肝损伤中起关键作用。在这项研究中，我们利用石胆酸刺激的HepG2人肝癌细胞，深入分析了胆管的形态学变化和绒毛蛋白在胆汁淤积中的生物学作用。我们证实肝移植患者胆汁淤积的肝切片胆小管破裂。石胆酸对HepG2细胞具有较强的细胞毒性，与细胞形态异常有关。石胆酸降低绒毛蛋白表达，在核受体激动剂存在下恢复。此外，小干扰RNA （siRNA）介导的核法氏体X受体和妊娠X受体敲低后，绒毛蛋白mRNA表达增加。使用siRNA敲低绒毛蛋白导致HepG2细胞生长停滞。采用DNA芯片技术分析绒毛蛋白敲低对HepG2细胞全基因组表达的影响。我们的数据表明，石胆酸通过farnesoid X受体和pregnane X受体抑制HepG2细胞中绒毛蛋白的表达，从而导致细胞生长停滞。
Cholestasis is a condition wherein bile flow is interrupted and lithocholic acid is known to play a key role in causing severe liver injury. In this study, we performed in-depth analysis of the morphological changes in bile canaliculi and the biological role of villin in cholestasis using lithocholic acid-stimulated HepG2 human hepatocarcinoma cells. We confirmed disruption of the bile canaliculi in liver sections from a liver allograft patient with cholestasis. Lithocholic acid caused strong cytotoxicity in HepG2 cells, which was associated with abnormal morphology. Lithocholic acid reduced villin expression, which recovered in the presence of nuclear receptor agonists. Furthermore, villin mRNA expression increased following small interfering RNA (siRNA)-mediated knockdown of the nuclear farnesoid X receptor and pregnane X receptor. Villin knockdown using siRNA caused cell growth arrest in HepG2 cells. The effect of villin-knockdown on whole-genome expression in HepG2 cells was analyzed by DNA microarray. Our data suggest that lithocholic acid caused cell growth arrest by suppressing villin expression via farnesoid X receptor and pregnane X receptor in HepG2 cells.