Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes.

Selenoprotein P (encoded by in humans, in rat), a liver-derived secretory protein, induces resistance to insulin and vascular endothelial growth factor (VEGF) in type 2 diabetes. Suppression of selenoprotein P may provide a novel therapeutic approach to treating type 2 diabetes; however, few drugs inhibiting expression in hepatocytes have been identified. The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by in rat) in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in promoter activity. EPA activated AMP-activated protein kinase (AMPK); however, the inhibitory effect of EPA on promoter activity was not canceled with an AMPK inhibitor compound C and dominant-negative AMPK transfection. Deletion mutant promoter assays and computational analysis of transcription factor-binding sites conserved among the species resulted in identification of a sterol regulatory element (SRE)-like site in the promoter. A chromatin immunoprecipitation (ChIP) assay revealed that EPA decreases binding of SREBP-1c to the promoter. Knockdown of resulted in a significant down-regulation of expression. Conversely, SREBP-1c overexpression inhibited the suppressive effect of EPA. These data provide a novel mechanism of action for EPA involving improvement of systemic insulin sensitivity through the regulation of selenoprotein P production independently of the AMPK pathway and suggest an additional approach to developing anti-diabetic drugs.