摘要
肝星状细胞(HSCs)的活化是肝纤维化病程进展中的核心环节。肝纤维化是一个可逆的病理过程,去除病因后,肝纤维化可以通过活化的HSCs凋亡和失活发生逆转。我们前期研究发现,蛋白酪氨酸磷酸酶1B(PTP1B)在肝纤维化进展期和逆转恢复期,可分别促进HSC活化和抑制aHSCs失活。但其在肝纤维化逆转期,对活化的HSCs凋亡的作用尚不明确。为了探究PTP1B对aHSCs凋亡的影响,本实验构建了小鼠肝纤维化及逆转模型;体外培养了大鼠肝星状细胞系HSC-T6, TGF-β1刺激活化后给予TRAIL诱导其凋亡以模拟肝纤维化逆转期aH SC凋亡过程。结果显示, PTP1B在肝纤维化肝组织中表达上调,而在纤维化自发恢复后表达降低。PTP1B在活化的HSC-T6中表达上调,在凋亡的aH SCs中表达下降。此外, PTP1B抑制了TRAIL的肝纤维化缓解效应,表现为过表达PTP1B后, TRAIL无法降低α-平滑肌肌动蛋白(α-SMA)及胶原蛋白的表达。同时,过表达PTP1B可以抑制TRAIL诱导的细胞凋亡,减少凋亡细胞的数量,降低凋亡蛋白的表达及活性。研究表明, PTP1B可以通过影响aH SCs的凋亡参与肝纤维化的逆转。
The activation of hepatic stellate cells(HSCs) is a key event in hepatic fibrosis(HF). As a reversible progress, HF can be reversed by inactivation and apoptosis of activated HSCs(aHSCs). We previously found that protein tyrosine phosphatase 1B(PTP1B) promotes HSC activation and inhibits aHSCs inactivation during the progressive and recovery stages of HF. Nevertheless, the effect of PTP1B on apoptosis of aHSCs remains unknown. Therefore, we investigated the link between PTP1B and aHSCs apoptosis. Mouse liver fibrosis and reversal models were established for this purpose. After activated by transforming growth factor-β1(TGF-β1), HSC-T6 cells were treated with TNF-related apoptosis-inducing ligand(TRAIL) to mimic apoptosis of aH SCs in vitro. The results showed that PTP1B was elevated in the fibrotic liver, but reduced after recovery. Consistently, PTP1B was highly-expressed in aHSCs, but declined in apoptotic aHSCs. Furthermore, PTP1B inhibited the alleviating effect of TRAIL in HF, indicating that TRAIL did not decrease collagen and α-smooth muscle actin(α-SMA) levels after PTP1B overexpression. Moreover, overexpression of PTP1B significantly restrained the pro-apoptotic effect of TRAIL, decreasing the number of apoptotic cells and apoptosis-related proteins. These observations revealed that PTP1B is involved in the reversal of HF by influencing the apoptosis of aHSCs.
作者
陈培杰
张云天
Peijie Chen;Yuntian Zhang(The First Affiliated Hospital of Anhui Medical University,Hefei 230012,Anhui,China;Anhui Public Health Clinical Center,Hefei 230012,Anhui,China;Hefei Jing-He Integrated Circuit Co.,LTD,Hefei 230012,Anhui,China;CAS Key Laboratory of Mechanical Behavior and Design of Materials,Department of Modern Mechanics,University of Science and Technology of China,Hefei 230027,Anhui,China)
基金
University Natural Science Research Project of Anhui Province (Grant No. KJ2020A0188)
Foundation of Anhui Medical University (Grant No. 2019xkj055)。
