Exposure to submicroplastics promotes the progression of nonalcoholic fatty liver disease in ApoE-deficient mice

Abstract

Microplastics (MPs) pose emerging threats to human health, with growing concerns about liver toxicity and other harmful effects from plastic particles. While aquatic species exhibit hepatic vulnerability to micro/nanoplastics, the role of submicroplastics (100 nm-1 μm) in mammalian non-alcoholic fatty liver disease (NAFLD) progression remains unclear. We investigated the effects of a 12-week exposure to 0.5 μm polystyrene MPs (submicroplastics) in drinking water, administering this to ApoE-deficient mice fed either a chow diet (CD) or a Western diet (WD). Submicroplastics accumulated predominantly in the liver and were excreted in the feces. Histologically, submicroplastics significantly increased NAFLD activity scores, hepatic steatosis (Oil Red O-positive area), and fibrosis (Masson-positive area), with maximal severity in the WD+MPs group. Also, the MPs exposure group had increases in positive areas for F4/80 and inflammatory markers TNF-α, IL-1β and IL-6 expression under both diets. Concurrently, submicroplastics inhibited antioxidant defenses by lowering levels of superoxide dismutase and glutathione, while also increasing the lipid peroxidation marker malondialdehyde. WD-fed mice exhibited pronounced MPs-induced lipid dysregulation, including elevated hepatic triglycerides, total cholesterol, and free fatty acids (FAs). Mechanistically, submicroplastics upregulated FA synthesis regulators (ACC, FASN, SREBP1) while downregulating FA oxidation mediators (CPT1A, ACOX1, PPARα) in the livers under a WD. Our findings demonstrate that chronic submicroplastics-exposure exacerbates the progression of NAFLD in ApoE-deficient mice by disturbing lipid metabolism, enhancing oxidative stress, and amplifying inflammatory responses. This study provides experimental evidence linking environmental plastic pollution to accelerated metabolic liver disease, thereby highlighting the urgent need for plastic exposure control strategies.