Abstract
Selenoprotein P (encoded by SELENOP in humans, Selenop 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 SELENOP expression in hepatocytes have been identified. The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses SELENOP expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by Srebf1 in rat) in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in SELENOP promoter activity. EPA activated AMP-activated protein kinase (AMPK); however, the inhibitory effect of EPA on SELENOP 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 SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay revealed that EPA decreases binding of SREBP-1c to the SELENOP promoter. Knockdown of Srebf1 resulted in a significant down-regulation of Selenop 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.
Highlights
Selenoprotein P, a liver-derived secretory protein, induces resistance to insulin and vascular endothelial growth factor (VEGF) in type 2 diabetes
The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses SELENOP expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by Srebf1 in rat) in H4IIEC3 hepatocytes
Because previous reports indicated that polyunsaturated fatty acids (PUFAs) down-regulate SREBP-1 via inhibition of nuclear translocation of SREBP-1 [33, 34], we confirmed the mechanism through which EPA inactivates SREBP-1c by examining the intracellular localization of SREBP-1c in EPA-treated H4IIEC3 hepatocytes
Summary
EPA caused concentration- and time-dependent suppression in Selenop mRNA expression, to the suppression of Srebf and fatty acid synthase (encoded by Fasn in rat), a. Similar to the results of mRNAs, EPA suppressed SELENOP promoter activity in a concentration- and time-dependent manner (Fig. 1, C and D). EPA treatment reduced SREBP-1c protein levels in the nuclear fraction in a concentration-dependent manner (Fig. 1E). Promoter activity of Mutant (Mut)-A, -B, -C, -D, and Normal, but not Mut-E, was suppressed by EPA treatment (Fig. 2A), indicating the existence of EPA-response element of the SELENOP promoter in Mut-D. The mature SREBP-1c overexpression especially inhibited the suppressive effect of EPA on SELENOP promoter activity (Fig. 3C); SREBP-1a overexpression had no effect (data not shown). These results suggest an association of SREBP-1c activity with the EPA-induced suppression of SELENOP expression.
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