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

探讨了新型磷脂介质溶血磷脂酸（LPA）及其合成酶autotaxin（ATX）在肝损伤中的临床意义。血清ATX活性和血浆LPA水平在与纤维化相关的慢性肝病中升高。血浆LPA水平与血清ATX活性相关，提示血清ATX活性是血浆LPA水平的决定因素之一。为了研究血清ATX活性和/或血浆LPA水平的增强是否普遍存在于肝损伤中，我们进行了动物模型研究。慢性四氯化碳（CCl_4）中毒大鼠血清ATX活性和血浆LPA水平升高与纤维化相关，其中CCl_4处理大鼠肝脏中ATX mRNA表达未发生改变，表明血清ATX活性增强可能不是由于肝脏转录水平上ATX产生增加所致。二甲基亚硝胺中毒急性肝损伤大鼠和70%去肝大鼠血清ATX活性和血浆LPA水平均升高。在二甲基亚硝胺中毒大鼠中，血清ATX活性与血清ALT水平相关，70%肝切除大鼠的血清ATX活性早在手术后3小时就增强，并在肝切除后24小时保持相同水平。这些结果表明，血清ATX活性和血浆LPA水平可能在肝损伤中普遍升高，与严重程度有关。肝损伤时血清ATX活性增强的机制可能与损害肝脏对ATX的清除减少有关。血清ATX活性和血浆LPA水平升高是单纯肝损伤的结果还是肝损伤的原因有待进一步明确。

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.