4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization
4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization
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DOI：
10.3390/ijms20246301
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Kotelevtsev, Yuri V.
中科院分区：
文献类型：
--
作者：
Andreichenko, Irina N.;Tsitrina, Alexandra A.;Kotelevtsev, Yuri V.
4-甲基伞形内酯(4MU)是一种透明质酸沉积的抑制剂，也是利胆、解痉药--月桂酮的活性物质。据报道，4MU在小鼠模型中具有抗纤维化作用；然而，确切的作用机制仍需进一步研究。在此，我们用NGS转录组、Q-PCR和免疫组织化学方法研究了4MU对CCl4诱导的小鼠肝纤维化作用的细胞和分子机制。4MU可抑制胶原和透明质酸沉积。CCl4刺激的COL1a和αSMA表达降低，而ECM分解代谢基因Hyal1的表达增加。生物信息学分析表明，CCl4处理可激活转化生长因子-β和Wnt/β-连环蛋白信号通路，抑制与脂代谢相关的基因，而4MU则将这些信号通路的关键标志恢复到对照水平。免疫组织化学分析显示4MU可抑制肝星状细胞(HSCs)向肌成纤维细胞的转分化。该药物影响肝干细胞和巨噬细胞在纤维化部位的定位。CCl4诱导FSTL1的表达，4MU可下调FSTL1的表达。我们的结果支持这一假设，即4MU通过减少透明质酸沉积和下调FSTL1的表达来减轻CCl4诱导的肝纤维化，同时抑制HSC的转分化和巨噬细胞定位的改变。
4-methylumbelliferone (4MU) is an inhibitor of hyaluronan deposition and an active substance of hymecromone, a choleretic and antispasmodic drug. 4MU reported to be anti-fibrotic in mouse models; however, precise mechanism of action still requires further investigation. Here we describe the cellular and molecular mechanisms of 4MU action on CCl4-induced liver fibrosis in mice using NGS transcriptome, Q-PCR and immunohistochemical analysis. Collagen and hyaluronan deposition were prevented by 4MU. The CCl4 stimulated expression of Col1a and alpha SMA were reduced, while the expression of the ECM catabolic gene Hyal1 was increased in the presence of 4MU. Bioinformatic analysis identified an activation of TGF-beta and Wnt/beta-catenin signaling pathways, and inhibition of the genes associated with lipid metabolism by CCL4 treatment, while 4MU restored key markers of these pathways to the control level. Immunohistochemical analysis reveals the suppression of hepatic stellate cells (HSCs) transdifferentiation to myofibroblasts by 4MU treatment. The drug affected the localization of HSCs and macrophages in the sites of fibrogenesis. CCl4 treatment induced the expression of FSTL1, which was downregulated by 4MU. Our results support the hypothesis that 4MU alleviates CCl4-induced liver fibrosis by reducing hyaluronan deposition and downregulating FSTL1 expression, accompanied by the suppression of HSC trans-differentiation and altered macrophage localization.