Elucidation of the mechanism of the inhibitory effect of sphingosine 1-phosphate on hepatocyte proliferation and the significance in liver regeneration

阐明1-磷酸鞘氨醇抑制肝细胞增殖的机制及其在肝再生中的意义

• 批准号: 14570451
• 负责人: IKEDA Hitoshi
• 金额: $ 2.3万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570451/
• 关键词: sphingosine 1-phosphate; Edg-5(S1P_2); Rho; liver regeneration; EDG5

Background & Aims: Sphingosine 1-phosphate (S1P), a ligand for G protein-coupled endothelial differentiation gene-I1(Edg-1), Edg-3, Edg-S, Edg-6 and Edg-8, elicits a variety of responses by cells: prominent among these is cell proliferation. S1P is abundantly stored in platelets and released upon their activation, suggesting that S1P plays a pathophysiological role in vivo. Because the major part of injected S1P was distributed into the liver in mice, we wondered whether the liver would be one of its targets. The effects of S1P on hepatocytes, the major constituent cells in the liver, were examined. Methods & Results: Northern blot analysis revealed the expression of Edg-1 and Edg-5 mRNAs in cultured rat hepatocytes, where S1P decreased DNA synthesis induced by HGF or EGF without affecting total protein synthesis. This inhibitory effect was attenuated by inactivation of small GTPase Rho with 03 exotoxin, but not by inactivation of G1 with pertussis toxin. Moreover, in the presence of JTE-013, a newly developed and specific binding antagonist for Edg-5, the inhibitory effect was also cancelled. Finally, the administration of S1P after 70% partial hepatectomy in rats reduced the peak of DNA synthesis in hepatocytes with increased Rho activity Furthermore, Edg-5 but not Edg-i mRNA expression was enhanced in hepatocytes 24-72 hours after partial hepatectomy, which coincides with decreasing hepatocyte. proliferation. Conclusions: S1P has an antiproliferative property in rat hepatocytes by activating Rho via Edg-5. Our results raise the possibility that S1P is a negative regulator in liver regeneration.

背景与目的：1-磷酸鞘氨醇 (S1P) 是 G 蛋白偶联内皮分化基因 I1(Edg-1)、Edg-3、Edg-S、Edg-6 和 Edg-8 的配体，可引起细胞多种反应：其中最突出的是细胞增殖。 S1P 大量储存在血小板中，并在血小板激活时释放，表明 S1P 在体内发挥病理生理学作用。由于注射的 S1P 的大部分分布在小鼠的肝脏中，我们想知道肝脏是否会成为其目标之一。检查了 S1P 对肝细胞（肝脏的主要组成细胞）的影响。方法和结果：Northern 印迹分析揭示了培养的大鼠肝细胞中 Edg-1 和 Edg-5 mRNA 的表达，其中 S1P 降低了 HGF 或 EGF 诱导的 DNA 合成，但不影响总蛋白合成。这种抑制作用可通过用 03 外毒素灭活小 GTP 酶 Rho 来减弱，但不会通过用百日咳毒素灭活 G1 来减弱。此外，在新开发的Edg-5特异性结合拮抗剂JTE-013的存在下，抑制作用也被取消。最后，大鼠70%部分肝切除术后给予S1P降低了肝细胞中DNA合成的峰值，同时Rho活性增加。此外，部分肝切除后24-72小时肝细胞中Edg-5而非Edg-i mRNA表达增强，这与肝细胞减少相一致。增殖。结论：S1P 通过 Edg-5 激活 Rho，在大鼠肝细胞中具有抗增殖特性。我们的结果提出了 S1P 是肝再生负调节因子的可能性。

项目成果

Ikeda H.: "Antiproliferative property of sphingosin 1-phosphate in rat hepatosytes involves activation of Rho via edg-5"Gastroenterology. 124(2). 459-469 (2003)

Ikeda H.：“大鼠肝细胞中 1-磷酸鞘氨醇的抗增殖特性涉及通过 edg-5 激活 Rho”胃肠病学。

Hitoshi Ikeda, Hiroaki Satob, Mikio Yanase, Yukiko Inoue, Tomoaki Tom ya, Masahiro Arai, Kazuaki Tejima, Kayo Nagashima, Hisato Maekawa, Naohisa Yahagi. Yutaka Yatomi, Soutaro Sakurada, Yoh Takuwa, Itsuro Ogata, Satoshi Kimura, Kenji Fujiwara: "Antiprolif

池田仁、佐藤弘明、柳濑干夫、井上由纪子、Tom ya智明、新井正宏、手岛和明、长岛佳代、前川久里、矢萩直久。

Ikeda H. et al.: "Antiproliferative property of sphingosine 1-phosphate in rat hepatocytes involves activation of Rho via Edg-5"Gastroenterology. 124. 459-469 (2003)

Ikeda H. 等人：“大鼠肝细胞中 1-磷酸鞘氨醇的抗增殖特性涉及通过 Edg-5 激活 Rho”胃肠病学。