Elucidation of the clinical significance of autotaxin and lysophosphatidic acid in liver diseases.

阐明自分泌运动因子和溶血磷脂酸在肝脏疾病中的临床意义。

• 批准号: 17590618
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590618/
• 关键词: Autotaxin; Lysophosphatidic acid; Liver fibrosis; Liver cirrhosis; Liver damage

The clinical significance of lysophosphatidic acid(LPA), a novel phospholipid mediator, and its synthetic enzyme, autotaxin(ATX) was investigated in liver damages. Serum ATX activity and plasma LPA level were determined to be elevated in human chronic liver diseases correlatively with fibrosis. Plasma LPA level was correlated with serum ATX activity, suggesting that serum ATX activity is one of the determinants of plasma LPA level. To investigate whether the enhancement of serum ATX activity and/or plasma LPA level might be generally found in liver damages, the study in animal models was performed. Serum ATX activity and plasma LPA level were enhanced in rats with chronic carbon tetrachloride(CCl_4) intoxication correlatively with fibrosis, where ATX mRNA expression was not altered in the liver of CCl_4-treated rats, indicating that enhancement of serum ATX activity may not be due to increased ATX production at the transcriptional level in the liver. Serum ATX activity and plasma LPA level were also increased in rats with acute liver injury due to dimethylnitrosamine intoxication or 70% hepatectomized rats. In rats with dimethylnitrosamine intoxication, serum ATX activity was correlated with serum ALT level, and in 70% hepatectomized rats, serum ATX activity was enhanced as early as 3 hours after the operation and sustained at the same level up to 24 hours after hepatectomy. These results suggest that serum ATX activity and plasma LPA level may be increased generally in liver damages in relation to the severity. The mechanism of enhancement of serum ATX activity in liver damages may involve the reduced clearance of ATX in damaged liver. Whether the increases of serum ATX activity and plasma LPA level may be simply the result of liver damages or the cause of liver damages should be further clarified.

探讨新型磷脂介体溶血磷脂酸(LPA)及其合成酶自体趋化蛋白(ATX)在肝损伤中的临床意义。慢性肝病患者血清ATX活性和血浆LPA水平明显升高，与肝纤维化程度密切相关。血浆LPA水平与血清ATX活性呈正相关，提示ATX活性是血浆LPA水平的决定因素之一。为了探讨肝损伤是否普遍存在血清ATX活性和/或血浆LPA水平的升高，本研究在动物模型上进行了研究。慢性四氯化碳(CCl_4)中毒大鼠血清ATX活性和血浆LPA水平升高与肝纤维化程度相关，而肝组织ATX mRNA表达无明显变化，提示血清ATX活性升高可能不是由于肝脏转录水平ATX生成增加所致。二甲基亚硝胺急性肝损伤大鼠和70%肝切除大鼠的血清ATX活性和血浆LPA水平也明显升高。二甲基亚硝胺中毒大鼠血清ATX活性与血清ALT水平呈正相关，70%肝切除大鼠血清ATX活性在术后3小时即开始升高，并持续至术后24小时。提示在肝损害中，血清ATX活性和血浆LPA水平普遍升高，且与病情严重程度相关。肝损伤时血清ATX活性升高的机制可能与ATX在受损肝脏的清除减少有关。血清ATX活性和血浆LPA水平升高可能是单纯肝损害的结果，还是肝损害的原因有待进一步阐明。