LXRα and PPARα Mediated Hepatic Lipid Metabolic Disruption Induced by the UV Filter EHMC in 2D and 3D HepaRG Cell Models

ABSTRACT

Ethylhexyl methoxycinnamate (EHMC), an important UVB filter, is raising concerns about its potential metabolic toxicity due to widespread human exposure through dietary sources. However, little is known about the effects of EHMC on hepatic lipid metabolism and the underlying mechanisms. In this study, we employed both 2D triglyceride assay and 3D high‐content imaging analysis to evaluate the hepatotoxicity and lipid accumulation potential for EHMC on HepaRG cells following 72h exposure, and further elucidated its underlying mechanisms. The results showed that EHMC at noncytotoxic concentrations significantly induced the accumulation of lipid droplets both in 2D and 3D cells. Biological assays revealed that EHMC induces the upregulation of two rate‐limiting enzymes within cells, thereby accelerating fatty acid synthesis. Meanwhile, there was no significant change in mitochondrial membrane potential. Western blot analysis revealed significantly increased protein levels of SREBP‐1 and nuclear receptors. Molecular docking analysis further revealed that EHMC binds well to three nuclear receptors. The results indicate that food‐derived EHMC can bind to nuclear receptors such as LXRα and PPARα, significantly disrupting hepatic lipid metabolism through the key factor SREBP‐1, thereby inducing the steatosis phenotype.