The lysophosphatidic acid (LPA) signaling axis is an important but rather underexplored pathway in liver disease. LPA is predominantly produced by Autotaxin (ATX) that has gained significant attention with an impressive number of ATX inhibitors (type I-IV) reported. Here, we evaluated the therapeutic potential of a (yet unexplored) type IV inhibitor, Cpd17, in liver injury. We first confirmed the involvement of the ATX-LPA signaling axis in human and murine diseased livers. Then, we evaluated the effects of Cpd17, in comparison with the classic type I inhibitor PF8380, in vitro, where Cpd17 showed higher efficacy. Thereafter, we characterized the mechanism-of-action of both inhibitors and found that Cpd17 was more potent in inhibiting RhoA-mediated cytoskeletal remodeling, and phosphorylation of MAPK/ERK and AKT/PKB. Finally, the therapeutic potential of Cpd17 was investigated in CCl₄-induced acute liver injury and diet-induced nonalcoholic steatohepatitis, demonstrating an excellent potential of Cpd17 in reducing liver injury in both disease models in vivo. We conclude that ATX inhibition, by type IV inhibitor in particular, has an excellent potential for clinical application in liver diseases.

中文翻译：

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IV 型 Autotaxin 抑制剂可改善急性肝损伤和非酒精性脂肪性肝炎


溶血磷脂酸 (LPA) 信号轴是肝脏疾病中一条重要但尚未充分探索的途径。 LPA 主要由自分泌运动因子 (ATX) 产生，随着大量 ATX 抑制剂（I-IV 型）的报道，ATX 引起了极大的关注。在这里，我们评估了一种（尚未探索的）IV 型抑制剂 Cpd17 在肝损伤中的治疗潜力。我们首先证实了 ATX-LPA 信号轴参与人类和小鼠患病肝脏。然后，我们在体外评估了 Cpd17 的效果，并与经典的 I 型抑制剂 PF8380 进行比较，其中 Cpd17 显示出更高的功效。此后，我们表征了两种抑制剂的作用机制，发现 Cpd17 在抑制 RhoA 介导的细胞骨架重塑以及 MAPK/ERK 和 AKT/PKB 磷酸化方面更有效。最后，研究了Cpd17在CCl ₄诱导的急性肝损伤和饮食诱导的非酒精性脂肪性肝炎中的治疗潜力，证明了Cpd17在体内减少两种疾病模型中肝损伤的优异潜力。我们得出的结论是，ATX 抑制，特别是 IV 型抑制剂的抑制，在肝脏疾病的临床应用中具有巨大的潜力。