Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
Biomolecules. 2023 Sep 28;13(10):1464. doi: 10.3390/biom13101464.
There has been a growing interest in studying the communication of gut microbial metabolites between the gut and the liver as liver fibrosis progresses. Although 3-Indolepropionic acid (IPA) is regarded as a clinically valuable gut metabolite for the treatment of certain chronic diseases, the effects of oral administration of IPA on hepatic fibrosis in different animal models have been conflicting. While some mechanisms have been proposed to explain these contradictory effects, the direct impact of IPA on hepatic fibrosis remains unclear. In this study, we found that IPA could directly activate LX-2 human hepatic stellate cells in vitro. IPA upregulated the expression of fibrogenic marker genes and promoted the features associated with HSCs activation, including proliferation and contractility. IPA also increased reactive oxygen species (ROS) in mitochondria and the expression of inflammation-related genes in LX-2 cells. However, when a ROS-blocking agent was used, these effects were reduced. p38 and JNK, the downstream signaling cascades of ROS, were found to be required for the activation of LX-2 induced by IPA. These findings suggest that IPA can directly activate hepatic stellate cells through ROS-induced JNK and p38 signaling pathways.
人们对研究肠道微生物代谢物在肠道和肝脏之间的通讯越来越感兴趣，因为肝纤维化在不断进展。虽然 3-吲哚丙酸（IPA）被认为是一种用于治疗某些慢性疾病的具有临床价值的肠道代谢物，但 IPA 对不同动物模型中肝纤维化的口服给药效果却存在争议。虽然已经提出了一些机制来解释这些矛盾的效果，但 IPA 对肝纤维化的直接影响仍不清楚。在这项研究中，我们发现 IPA 可以在体外直接激活 LX-2 人肝星状细胞。IPA 上调了致纤维化标记基因的表达，并促进了与 HSCs 激活相关的特征，包括增殖和收缩性。IPA 还增加了 LX-2 细胞中线粒体中的活性氧（ROS）和炎症相关基因的表达。然而，当使用 ROS 阻断剂时，这些效果会降低。ROS 的下游信号级联 p38 和 JNK 被发现是 IPA 诱导的 LX-2 激活所必需的。这些发现表明，IPA 可以通过 ROS 诱导的 JNK 和 p38 信号通路直接激活肝星状细胞。
