Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201306, China; Key Laboratory of Ministry of Education, College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai 201306, China.
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai 201306, China.
Acta Trop. 2020 Jun;206:105449. doi: 10.1016/j.actatropica.2020.105449. Epub 2020 Mar 16.
Lipoic acid (LA) has been shown to possess protective effects against liver fibrosis mainly by induction of apoptosis of activated hepatic stellate cells, but the mechanism of LA activity in liver fibrosis has yet to be completely explained. LA occurs naturally in mitochondria as a coenzyme. In this study, we used mice with schistosomiasis-induced liver fibrosis and mouse hepatocarcinoma cell line 1C1C7 as models to investigate the mitochondrial mechanism of LA treatment for liver fibrosis. Western blot, real-time PCR and oxygen consumption rate (OCR) test were used. In the livers of mice with liver fibrosis, the mRNA levels of LA synthetic pathway enzymes, including MCAT, OXSM, MECR, and LIAS, were significantly reduced. Livers of mice with liver fibrosis showed degenerative signs, such as mitochondrial edema, a reduced mitochondrial crest and matrix density, or vacuolation; the activities of mitochondrial complexes I, II, IV, and V were also decreased in these livers. The expression of phosphorylation Drp1 (p-Drp1) was decreased in the livers of mice with liver fibrosis, indicating increased mitochondrial fission activity, whereas OPA1 and MFN1 expression was reduced, denoting decreased activity of mitochondrial fusion. To understand the mitochondrial mechanism of LA treatment for liver fibrosis, p-Drp1, OPA1, and MFN1 expression were detected at the protein level in mouse hepatocarcinoma cell line 1C1C7 stimulated by LA. OPA1 and MFN1 were not significantly altered, but p-Drp1 was significantly increased. The results suggest that LA may alleviate liver fibrosis through upregulating p-Drp1. This study provides a new insight into the mechanism of the protective effect of LA against schistosomiasis-induced liver fibrosis, which demonstrates that LA is required for the maintenance of mitochondrial function by upregulating p-Drp1 expression to inhibit mitochondrial fission.
硫辛酸（LA）已被证明具有抗肝纤维化的保护作用，主要通过诱导活化的肝星状细胞凋亡来实现，但 LA 治疗肝纤维化的机制尚未完全阐明。LA 作为辅酶在线粒体中自然存在。在这项研究中，我们使用日本血吸虫病诱导的肝纤维化小鼠模型和小鼠肝癌细胞系 1C1C7 作为模型，研究 LA 治疗肝纤维化的线粒体机制。使用 Western blot、实时 PCR 和耗氧率（OCR）测试。在肝纤维化小鼠的肝脏中，LA 合成途径酶的 mRNA 水平，包括 MCAT、OXSM、MECR 和 LIAS，均显著降低。肝纤维化小鼠的肝脏出现退行性变化，如线粒体水肿、嵴和基质密度减少或空泡化；这些肝脏中的线粒体复合物 I、II、IV 和 V 的活性也降低。肝纤维化小鼠肝脏中磷酸化 Drp1（p-Drp1）的表达减少，表明线粒体分裂活性增加，而 OPA1 和 MFN1 的表达减少，表明线粒体融合活性降低。为了了解 LA 治疗肝纤维化的线粒体机制，在 LA 刺激的小鼠肝癌细胞系 1C1C7 中检测了 p-Drp1、OPA1 和 MFN1 的蛋白水平。OPA1 和 MFN1 没有明显改变，但 p-Drp1 明显增加。结果表明，LA 可能通过上调 p-Drp1 来减轻肝纤维化。这项研究为 LA 对日本血吸虫病诱导的肝纤维化的保护作用机制提供了新的见解，表明 LA 通过上调 p-Drp1 表达来维持线粒体功能，从而抑制线粒体分裂。
