Hepatic ZIP8 deficiency is associated with disrupted selenium homeostasis, liver pathology, and tumor formation

氧化应激 平衡 炎症 化学 免疫组织化学 肝损伤 肝细胞 抗氧化剂 硒缺乏症 内科学 病理 内分泌学 医学 生物化学 超氧化物歧化酶 谷胱甘肽过氧化物酶 有机化学 体外
作者
Liu Liu,Xiangrong Geng,Yihong Cai,Bryan L. Copple,Masahiro Yoshinaga,Jian‐Ren Shen,Daniel W. Nebert,Hua Wang,Zijuan Liu
出处
期刊:American Journal of Physiology-gastrointestinal and Liver Physiology [American Physiological Society]
卷期号:315 (4): G569-G579 被引量:24
标识
DOI:10.1152/ajpgi.00165.2018
摘要

Zrt/Irt-like protein 8 (ZIP8) (encoded by Slc39a8) is a multifunctional membrane transporter that influxes essential metal cations Zn 2+ , Mn 2+ , Fe 2+ , and nonmetal inorganic selenite (HSeO 3 − ). Physiological roles of ZIP8 in different cell types and tissues remain to be elucidated. We aimed to investigate ZIP8 functions in liver. Two mouse models were used in this study: 1) 13- to 21-mo-old Slc39a8(+/neo) hypomorphs having diminished ZIP8 levels and 2) a liver-specific ZIP8 acute knockdown mouse (Ad-shZip8). Histology, immunohistochemistry, and Western blotting were used to investigate ZIP8-deficiency effects on hepatic injury, inflammatory changes, and oxidative stress. Selenium (Se) and zinc (Zn) were quantified in tissues by inductively coupled plasma-mass spectrophotometry. We found that ZIP8 is required to maintain normal liver function; moderate or acute decreases in ZIP8 activity resulted in hepatic pathology. Spontaneous liver neoplastic nodules appeared in ~50% of Slc39a8(+/neo) between 13 and 21 mo of age, exhibiting features of inflammation, fibrosis, and liver injury. In Ad-shZip8 mice, significant hepatomegaly was observed; histology showed ZIP8 deficiency was associated with hepatocyte injury, inflammation, and proliferation. Significant decreases in Se, but not Zn, were found in Ad-shZip8 liver. Consistent with this Se deficit, liver expression of selenoproteins glutathione peroxidases 1 and 2 was downregulated, along with decreases in antioxidant superoxide dismutases 1 and 2, consistent with increased oxidative stress. Thus, ZIP8 plays an important role in maintaining normal hepatic function, likely through regulating Se homeostasis and redox balance. Hepatic ZIP8 deficiency is associated with liver pathology, including oxidative stress, inflammation, proliferation, and hepatocellular injury. NEW & NOTEWORTHY Zrt/Irt-like protein 8 (ZIP8) is a multifunctional membrane transporter that facilitates biometal and mineral uptake. The role of ZIP8 in liver physiology has not been previously investigated. Liu et al. discovered unique ZIP8 functions, i.e., regulation of hepatic selenium content and association of ZIP8 deficiency in mouse liver with liver defects.
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