Abstract

Nonalcoholic fatty liver disease (NAFLD) is the leading hepatic manifestation of metabolic syndrome worldwide, and is clinically accompanied by iron overload. As the increasing application of iron oxide nanoparticles (IONPs) on the imaging and diagnosis in NAFLD, the potential hepatic effect and mechanism of IONPs on NAFLD should be well studied. Here, we demonstrate that carboxyl-modified (COOH-IONPs) and amino-coated IONPs (NH₂-IONPs) exhibit no significant hepatic toxicity in normal mice at the clinical injection dose, but aggravate SREBP-1c-mediated de novo lipogenesis (DNL) in the livers of mice with NAFLD induced by high-fat diet (HFD) and in HepG2 cells incubated with oleic acid (OA), especially in those treated by the positive NH₂-IONPs. In the present study, mice receiving IONPs for 7 day show mild iron overload in the liver and exhibit enhanced hepatic inflammation in NAFLD. The BMP-SMAD pathway is initiated by hepatic iron overload and is aggravated in NAFLD. In conclusion, BMP-SMAD-mediated hepatic iron overload aggravated lipid accumulation in the liver and hepatic inflammatory responses, implying that effective measures in addition to hepatic iron overload are needed for individuals at the risk of IONPs in NAFLD.

摘要

非酒精性脂肪性肝病 (NAFLD) 是世界范围内代谢综合征的主要肝脏表现，临床上伴有铁过载。随着氧化铁纳米颗粒 (IONPs) 在 NAFLD 成像和诊断中的应用越来越多，应深入研究 IONPs 对 NAFLD 的潜在肝脏作用和机制。在这里，我们证明羧基修饰的 (COOH-IONPs) 和氨基包覆的 IONPs (NH ₂ -IONPs) 在临床注射剂量下对正常小鼠没有显着的肝毒性，但会加剧 SREBP-1c 介导的从头脂肪生成 (DNL) ) 在高脂肪饮食 (HFD) 诱导的 NAFLD 小鼠的肝脏和油酸 (OA) 孵育的 HepG2 细胞中，尤其是在那些接受阳性 NH ₂治疗的细胞中-IONPs。在本研究中，接受 IONPs 7 天的小鼠在肝脏中表现出轻度铁过载，并在 NAFLD 中表现出增强的肝脏炎症。BMP-SMAD 通路由肝脏铁过载启动，并在 NAFLD 中加重。总之，BMP-SMAD 介导的肝脏铁超负荷加重了肝脏中的脂质积累和肝脏炎症反应，这意味着除了肝脏铁超负荷外，还需要对 NAFLD 中存在 IONP 风险的个体采取有效措施。