Translational Liver Research, Department of Medical Cell BioPhysics, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
Oncode Institute, Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands.
EMBO Mol Med. 2022 Sep 7;14(9):e16333. doi: 10.15252/emmm.202216333. Epub 2022 Jul 14.
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 CCl -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.
溶血磷脂酸（LPA）信号轴是肝脏疾病中一个重要但尚未充分研究的途径。LPA 主要由 Autotaxin（ATX）产生，由于报道了大量的 ATX 抑制剂（I 型-IV 型），ATX 引起了人们的极大关注。在这里，我们评估了一种（尚未探索）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 信号轴在人类和小鼠患病肝脏中的参与。然后，我们评估了 Cpd17 的效果，与经典的 I 型抑制剂 PF8380 进行了比较，发现 Cpd17 在体外具有更高的疗效。此后，我们对两种抑制剂的作用机制进行了表征，发现 Cpd17 在抑制 RhoA 介导的细胞骨架重塑以及 MAPK/ERK 和 AKT/PKB 的磷酸化方面更为有效。最后，我们研究了 Cpd17 在 CCl 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，结果表明 Cpd17 在体内两种疾病模型中均具有降低肝损伤的良好潜力。我们得出结论，ATX 抑制，特别是 IV 型抑制剂，在肝脏疾病的临床应用中具有极好的潜力。
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