PM2.5 promotes Drp1-mediated mitophagy to induce hepatic stellate cell activation and hepatic fibrosis via regulating miR-411,Experimental Cell Research

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PM2.5 promotes Drp1-mediated mitophagy to induce hepatic stellate cell activation and hepatic fibrosis via regulating miR-411
Experimental Cell Research ( IF 3.7 ) Pub Date : 2021-09-08 , DOI: 10.1016/j.yexcr.2021.112828
Zhong-Jian Wang ₁ , Hui Yu ₁ , Jin-Jin Hao ₁ , Yun Peng ₁ , Tian-Tian Yin ₁ , Yi-Ning Qiu ₁

Affiliation

Background

Particulate matter≤ 2.5 μm (PM_2.5) is a type of environmental agent associated with air pollution, which induces hepatic fibrosis. However, the function and mechanism of PM_2.5 on hepatic stellate cell (HSC) proliferation and fibrosis remain largely unknown.

Methods

Human HSC line (LX-2) and murine HSCs were exposed to various doses of PM_2.5. microRNA (miR)-411 expression was detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, fibrosis, mitochondrial dynamics dysfunction and mitophagy were determined via cell counting kit-8 (CCK-8), qRT-PCR, Western blotting and immunofluorescence.

Results

PM_2.5 facilitated HSC proliferation and fibrosis via increasing the levels of ACTA2, Collagen 1, TIMP1 and TGF-β1. PM_2.5 reduced miR-411 expression, and contributed to mitochondrial dynamics dysfunction via increasing Drp1 and decreasing OPA1, TOM20 and PGC-1α levels. PM_2.5 promoted mitophagy by upregulating the levels of Beclin-1, LC3II/I, PINK1 and Parkin. miR-411 overexpression or autophagy blockage using 3-methyladenine (3-MA) relieved PM_2.5-mediated cell proliferation and fibrosis-associated factor expression in HSCs. Drp1 was targeted by miR-411. miR-411 mitigated PM_2.5-induced mitophagy via targeting Drp1. Drp1 overexpression abolished the inhibitory role of miR-411 in cell proliferation and fibrosis-associated factor levels in HSCs.

Conclusion

PM_2.5 induced HSC activation and fibrosis via promoting Drp1-mediated mitophagy by decreasing miR-411, thereby causing liver fibrosis.

中文翻译：

PM2.5通过调节miR-411促进Drp1介导的线粒体自噬诱导肝星状细胞活化和肝纤维化

背景

颗粒物≤ 2.5 μm (PM _2.5 ) 是一种与空气污染相关的环境因子，可诱发肝纤维化。然而，PM _2.5对肝星状细胞 (HSC) 增殖和纤维化的功能和机制仍然未知。

方法

人 HSC 系 (LX-2) 和鼠 HSC 暴露于不同剂量的 PM _2.5。通过定量逆转录聚合酶链反应 (qRT-PCR) 检测 microRNA (miR)-411 表达。通过细胞计数试剂盒-8 (CCK-8)、qRT-PCR、蛋白质印迹和免疫荧光测定细胞增殖、纤维化、线粒体动力学功能障碍和线粒体自噬。

结果

PM _2.5通过增加 ACTA2、胶原蛋白 1、TIMP1 和 TGF-β1 的水平促进 HSC 增殖和纤维化。PM _2.5降低 miR-411 表达，并通过增加 Drp1 和降低 OPA1、TOM20 和 PGC-1α 水平导致线粒体动力学功能障碍。PM _2.5通过上调 Beclin-1、LC3II/I、PINK1 和 Parkin 的水平来促进线粒体自噬。使用 3-甲基腺嘌呤 (3-MA) 的 miR-411 过表达或自噬阻断减轻了 HSC 中PM _2.5介导的细胞增殖和纤维化相关因子的表达。Drp1 是 miR-411 的目标。miR-411 减轻 PM _2.5-通过靶向 Drp1 诱导线粒体自噬。Drp1 过表达消除了 miR-411 在 HSC 细胞增殖和纤维化相关因子水平中的抑制作用。