High CYP2E1 activity aggravates hepatofibrosis by limiting macrophage polarization towards the M2 phenotype
High CYP2E1 activity aggravates hepatofibrosis by limiting macrophage polarization towards the M2 phenotype
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高 CYP2E1 活性通过限制巨噬细胞向 M2 表型极化而加剧肝纤维化
DOI：
10.1002/mc.23029
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发表时间：
2019-08-01
影响因子：
4.6
通讯作者：
Qiao, Hai-ling
中科院分区：
文献类型：
--
作者：
Guo, Yuan-yuan;Xu, Chen;Qiao, Hai-ling
细胞色素P450 2E1 （CYP2E1）是一种重要的药物代谢酶，已被认为是肝纤维化的危险因素之一。巨噬细胞在调节肝纤维化的进展和消退中起关键作用。然而，CYP2E1是否参与肝纤维化过程中巨噬细胞极化的调节尚不清楚。在这里，我们测量了CYP2E1活性以及CD163（一种M2标记物）和CD68（一种泛巨噬细胞标记物）在肝癌患者肝纤维化组织（n = 26）中的表达，并与正常肝组织（n = 26）进行比较。在二乙基亚硝胺（DEN）处理的Sprague-Dawley大鼠中，评估体内CYP2E1活性与CD163/CD68比值（M2极化指标）以及肝纤维化程度的关系。引人注目的是，CYP2E1活性和CD68表达增加，CD163/CD68比值降低，特别是在CYP2E1活性较高的肝纤维化组织中。α - sma、Ki67和PCNA的表达与CYP2E1活性呈正相关，与CD163/CD68比值呈负相关。此外，CYP2E1活性与CD163/CD68比值呈负相关。总体而言，高CYP2E1活性通过抑制M2巨噬细胞极化而加重肝纤维化，为了解CYP2E1的促纤维化活性提供了新的见解，并为肝纤维化治疗提供了有希望的途径。
Cytochrome P450 2E1 (CYP2E1) is an important drug-metabolizing enzyme that has been recognized as one of the risk factors for hepatofibrosis. Macrophages play key roles in regulating hepatofibrosis progression and resolution. However, whether CYP2E1 is involved in the regulation of macrophage polarization during hepatofibrosis is still unclear. Herein, we measured CYP2E1 activity and the expression of CD163 (an M2 marker) and CD68 (a pan-macrophage marker) in hepatofibrotic tissue from HCC patients (n = 26) with comparison to normal liver tissue (n = 26). The relationship of CYP2E1 activity in vivo and the CD163/CD68 ratio (an indicator of M2 polarization), as well as the extent of hepatofibrosis, were evaluated in diethylnitrosamine (DEN)-treated Sprague-Dawley rats. Strikingly, CYP2E1 activity and expression of CD68 increased and the CD163/CD68 ratio decreased, especially in hepatofibrotic tissue with higher CYP2E1 activity. Expression of alpha-SMA, Ki67, and PCNA were positively correlated with CYP2E1 activity and inversely correlated with the CD163/CD68 ratio. Furthermore, CYP2E1 activity showed an inverse correlation with the CD163/CD68 ratio. Overall, high CYP2E1 activity aggravates hepatofibrosis by restraining M2 macrophage polarization, providing a novel insight for understanding the profibrotic activity of CYP2E1 and a promising avenue for hepatofibrosis therapy.