Hepatogenomics Research Group, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Australia.
Hepatogenomics Research Group, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, Australia.
Biochim Biophys Acta Mol Basis Dis. 2020 Oct 1;1866(10):165882. doi: 10.1016/j.bbadis.2020.165882. Epub 2020 Jun 18.
Peroxisomes are organelles, abundant in the liver, involved in a variety of cellular functions, including fatty acid metabolism, plasmalogen synthesis and metabolism of reactive oxygen species. Several inherited disorders are associated with peroxisomal dysfunction; increasingly many are associated with hepatic pathologies. The liver plays a principal role in regulation of iron metabolism. In this study we examined the possibility of a relationship between iron homeostasis and peroxisomal integrity. We examined the effect of deleting Pex13 in mouse liver on systemic iron homeostasis. We also used siRNA-mediated knock-down of PEX13 in a human hepatoma cell line (HepG2/C3A) to elucidate the mechanisms of PEX13-mediated regulation of hepcidin. We demonstrate that transgenic mice lacking hepatocyte Pex13 have defects in systemic iron homeostasis. The ablation of Pex13 expression in hepatocytes leads to a significant reduction in hepatic hepcidin levels. Our results also demonstrate that a deficiency of PEX13 gene expression in HepG2/C3A cells leads to decreased hepcidin expression, which is mediated through an increase in the signalling protein SMAD7, and endoplasmic reticulum (ER) stress. This study identifies a novel role for a protein involved in maintaining peroxisomal integrity and function in iron homeostasis. Loss of Pex13, a protein important for peroxisomal function, in hepatocytes leads to a significant increase in ER stress, which if unresolved, can affect liver function. The results from this study have implications for the management of patients with peroxisomal disorders and the liver-related complications they may develop.
过氧化物酶体是一种细胞器，在肝脏中丰富存在，参与多种细胞功能，包括脂肪酸代谢、类脂素合成和活性氧代谢。几种遗传性疾病与过氧化物酶体功能障碍有关；越来越多的疾病与肝脏病理有关。肝脏在铁代谢的调节中起着主要作用。在这项研究中，我们研究了铁稳态和过氧化物酶体完整性之间可能存在的关系。我们研究了在小鼠肝脏中敲除 Pex13 对全身铁稳态的影响。我们还使用 siRNA 介导的人肝癌细胞系 (HepG2/C3A) 中的 PEX13 敲低来阐明 PEX13 介导的铁调素调节的机制。我们证明缺乏肝细胞 Pex13 的转基因小鼠存在全身铁稳态缺陷。肝细胞中 Pex13 表达的缺失导致肝脏铁调素水平显著降低。我们的结果还表明，HepG2/C3A 细胞中 PEX13 基因表达的缺乏导致铁调素表达减少，这是通过信号蛋白 SMAD7 的增加和内质网 (ER) 应激介导的。这项研究确定了一种参与维持过氧化物酶体完整性和功能的蛋白质在铁稳态中的新作用。肝细胞中过氧化物酶体功能重要的 Pex13 蛋白缺失会导致 ER 应激显著增加，如果得不到解决，可能会影响肝功能。这项研究的结果对患有过氧化物酶体疾病的患者的管理以及他们可能发展的肝脏相关并发症具有重要意义。
