Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, PR China.
Exp Cell Res. 2021 Oct 15;407(2):112828. doi: 10.1016/j.yexcr.2021.112828. Epub 2021 Sep 8.
Particulate matter≤ 2.5 μm (PM) is a type of environmental agent associated with air pollution, which induces hepatic fibrosis. However, the function and mechanism of PM on hepatic stellate cell (HSC) proliferation and fibrosis remain largely unknown.
Human HSC line (LX-2) and murine HSCs were exposed to various doses of PM. 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.
PM facilitated HSC proliferation and fibrosis via increasing the levels of ACTA2, Collagen 1, TIMP1 and TGF-β1. PM reduced miR-411 expression, and contributed to mitochondrial dynamics dysfunction via increasing Drp1 and decreasing OPA1, TOM20 and PGC-1α levels. PM 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-mediated cell proliferation and fibrosis-associated factor expression in HSCs. Drp1 was targeted by miR-411. miR-411 mitigated PM-induced mitophagy via targeting Drp1. Drp1 overexpression abolished the inhibitory role of miR-411 in cell proliferation and fibrosis-associated factor levels in HSCs.
PM induced HSC activation and fibrosis via promoting Drp1-mediated mitophagy by decreasing miR-411, thereby causing liver fibrosis.
粒径≤2.5μm（PM）是一种与空气污染有关的环境因子，可诱导肝纤维化。然而，PM 对肝星状细胞（HSC）增殖和纤维化的作用及机制仍知之甚少。
将人 HSC 系（LX-2）和鼠 HSCs 暴露于不同剂量的 PM 中。采用实时定量逆转录聚合酶链反应（qRT-PCR）检测 microRNA（miR）-411 的表达。通过细胞计数试剂盒-8（CCK-8）、qRT-PCR、Western blot 和免疫荧光检测细胞增殖、纤维化、线粒体动力学功能障碍和自噬。
PM 通过增加 ACTA2、Collagen 1、TIMP1 和 TGF-β1 的水平促进 HSC 增殖和纤维化。PM 降低了 miR-411 的表达，并通过增加 Drp1 和降低 OPA1、TOM20 和 PGC-1α 的水平导致线粒体动力学功能障碍。PM 通过上调 Beclin-1、LC3II/I、PINK1 和 Parkin 的水平促进自噬。miR-411 过表达或使用 3-甲基腺嘌呤（3-MA）阻断自噬可减轻 PM 介导的 HSCs 增殖和纤维化相关因子表达。Drp1 是 miR-411 的靶标。miR-411 通过靶向 Drp1 减轻 PM 诱导的自噬。Drp1 过表达消除了 miR-411 对 HSCs 增殖和纤维化相关因子水平的抑制作用。
PM 通过降低 miR-411 促进 Drp1 介导的自噬，诱导 HSC 活化和纤维化，从而导致肝纤维化。
