Microplastics, particularly polymethyl methacrylate (PMMA), have emerged as significant environmental pollutants, with growing concerns about their impact on various biological processes. However, the effects of chronic PMMA exposure on hepatic lipid metabolism remain insufficiently studied. This research aimed to examine the consequences of chronic exposure to PMMA particles of different sizes (100 nm and 2 μm) on hepatic lipid metabolism in mice. Female C57BL/6J mice were administered PMMA particles in drinking water over an 8-week period, and the effects on intestinal and liver morphology and function were evaluated. Histopathological analyses, gut microbiota profiling, and serum and liver assays were conducted to assess oxidative stress, lipid metabolism-related biomarkers, and liver metabolomics. The results revealed that PMMA particles accumulated in both the liver and colon, causing liver injury characterized by elevated ALT and AST levels. The exposure also induced oxidative stress by inhibiting the NRF2/HO-1 signaling pathway. Furthermore, PMMA exposure resulted in significant alterations to the gut microbiota and hepatic metabolism. These changes were linked to increased microbial diversity, which impacted cholesterol metabolism through the gut-liver axis. Additionally, the activation of the PI3K/AKT/PPARγ signaling pathway disrupted hepatic lipid metabolism, leading to increased cholesterol synthesis and hepatic lipid accumulation. This study underscores the potential of PMMA to disrupt both hepatic lipid metabolism and gut microbiota composition, suggesting a novel mechanism by which PMMA exposure could contribute to metabolic disorders and liver disease. © 2025 Elsevier Ltd
