Hepatocyte-specific deletion of peroxisomal protein PEX13 results in disrupted iron homeostasis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Rishi, Gautam¹  Bhatia, Maneet¹  Secondes, Eriza S.¹  Melino, Michelle¹  Crane, Denis, I²  Subramaniam, V. Nathan¹ 

[1] Queensland Univ Technol QUT, Sch Biomed Sci, Inst Hlth & Biomed Innovat, Hepatogen Res Grp, Brisbane, Qld, Australia

[2] Griffith Univ, Sch Environm & Sci, Brisbane, Qld, Australia

关键词: Iron metabolism;    Hemochromatosis;    Peroxisomal disorders;    Genetic modifiers;    Iron overload;   

DOI  :  10.1016/j.bbadis.2020.165882

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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