Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Central laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, China.
Central laboratory, Shanghai Sixth People's Hospital East Campus, Shanghai University of Medicine & Health Sciences, Shanghai, China; National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai, China.
Acta Trop. 2021 Feb;214:105781. doi: 10.1016/j.actatropica.2020.105781. Epub 2020 Nov 29.
Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. Inhibition of the HSCs activity is an ideal strategy in the treatment of fibrosis, but there is no drug yet for this strategy. Artesunate (ART) has been shown to protect liver from fibrosis through inhibition of HSCs activity. However, the mechanism of ART activity remains to be fully uncovered. In this study, we tested ART in a mouse model of hepatic fibrosis established in the schistosomiasis-infected mice. The mechanism of ART action was investigated in the HSC cell line LX-2. ART significantly inhibited hepatic fibrosis. In LX-2 cells, ART efficiently inhibited the cell activity in proliferation and mRNA expression of fibrosis marker genes including Col1a1 and Col3a1. An impact of ART on mitochondria was observed for suppression of enzymes in the citric acid cycle (TCA), such as citrate synthase (CS), isocitrate dehydrogenase (IDH), and alpha ketoglutarate dehydrogenase (OGDH) in a dose-dependent manner. ART decreased the mitochondrial oxygen consumption rate (OCR) and the protein levels of mitochondrial complex Ⅰ subunit NDUFB8 and complex Ⅲ subunit UQCRC2 in HSCs. All of these alterations were observed with an increase in HSC apoptosis. This study suggests that ART may alleviate liver fibrosis by downregulation of HSC activity through suppression of NDUFB8 and UQCRC2 in mitochondria. This study provides a new insight into the mechanism of the ART activity in the inhibition of schistosomiasis-induced liver fibrosis.
肝星状细胞（HSCs）在肝纤维化的发病机制中起关键作用。抑制 HSCs 的活性是治疗纤维化的理想策略，但目前还没有针对这种策略的药物。青蒿琥酯（ART）已被证明通过抑制 HSCs 的活性来保护肝脏免受纤维化的影响。然而，ART 的作用机制仍有待充分揭示。在本研究中，我们在感染血吸虫病的小鼠建立的肝纤维化小鼠模型中测试了 ART。在 HSC 细胞系 LX-2 中研究了 ART 的作用机制。ART 显著抑制肝纤维化。在 LX-2 细胞中，ART 有效地抑制了细胞增殖活性和纤维化标志物基因（包括 Col1a1 和 Col3a1）的 mRNA 表达。ART 对柠檬酸循环（TCA）中的酶，如柠檬酸合酶（CS）、异柠檬酸脱氢酶（IDH）和α-酮戊二酸脱氢酶（OGDH），具有抑制作用，呈剂量依赖性。ART 降低了 HSCs 的线粒体耗氧率（OCR）和线粒体复合物Ⅰ亚基 NDUFB8 和复合物Ⅲ亚基 UQCRC2 的蛋白水平。所有这些改变都伴随着 HSC 凋亡的增加而观察到。本研究表明，ART 可能通过抑制线粒体中的 NDUFB8 和 UQCRC2 下调 HSC 活性来缓解肝纤维化。本研究为 ART 抑制血吸虫病诱导的肝纤维化的作用机制提供了新的见解。
