Iron oxide nanoparticles aggravate hepatic steatosis and liver injury in nonalcoholic fatty liver disease through BMP-SMAD-mediated hepatic iron overload.

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.