Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwakecho, Kyoto, 606-8502, Japan.
Laboratory of Veterinary Anatomy, Kitasato University School of Veterinary Medicine, Towada, 034-8628, Japan.
Sci Rep. 2020 Dec 3;10(1):21184. doi: 10.1038/s41598-020-78026-6.
Iron is essential for a variety of physiological processes. Hepatic iron overload acts as a trigger for the progression of hepatic steatosis to nonalcoholic steatohepatitis and hepatocellular carcinoma. In the present study, we aimed to study the effects of iron overload on cellular responses in hepatocytes. Rat primary hepatocytes (RPH), mouse primary hepatocytes (MPH), HepG2 human hepatoma cells and Hepa1-6 mouse hepatoma cells were treated with FeCl. Treatment with FeCl effectively increased iron accumulation in primary hepatocytes. Expression levels of molecules involved in cellular signaling such as AMPK pathway, TGF-β family pathway, and MAP kinase pathway were decreased by FeCl treatment in RPH. Cell viability in response to FeCl treatment was decreased in RPH but not in HepG2 and Hepa1-6 cells. Treatment with FeCl also decreased expression level of LC-3B, a marker of autophagy in RPH but not in liver-derived cell lines. Ultrastructural observations revealed that cell death resembling ferroptosis and necrosis was induced upon FeCl treatment in RPH. The expression level of genes involved in iron transport varied among different liver-derived cells- iron is thought to be efficiently incorporated as free Fe in primary hepatocytes, whereas transferrin-iron is the main route for iron uptake in HepG2 cells. The present study reveals specific cellular responses in different liver-derived cells as a consequence of iron overload.
铁是多种生理过程所必需的。肝脏铁过载作为肝脂肪变性向非酒精性脂肪性肝炎和肝细胞癌进展的触发因素。在本研究中，我们旨在研究铁过载对肝细胞中细胞反应的影响。用 FeCl 处理大鼠原代肝细胞 (RPH)、小鼠原代肝细胞 (MPH)、HepG2 人肝癌细胞和 Hepa1-6 小鼠肝癌细胞。FeCl 处理有效增加了原代肝细胞中的铁积累。AMPK 途径、TGF-β 家族途径和 MAP 激酶途径等细胞信号分子的表达水平在 RPH 中因 FeCl 处理而降低。RPH 中对 FeCl 处理的细胞活力降低，但 HepG2 和 Hepa1-6 细胞中没有。FeCl 处理还降低了 RPH 中自噬标志物 LC-3B 的表达水平，但在肝源性细胞系中没有。超微结构观察显示，RPH 中细胞死亡类似于铁死亡和坏死，这是由 FeCl 处理引起的。不同肝源性细胞中铁转运相关基因的表达水平不同——铁被认为在原代肝细胞中作为游离铁有效地被摄取，而转铁蛋白-铁是 HepG2 细胞中铁摄取的主要途径。本研究揭示了铁过载后不同肝源性细胞中特定的细胞反应。
