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J Biol Chem. 2017 Jun 30;292(26):10791-10800. doi: 10.1074/jbc.M116.747006. Epub 2017 May 2.

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.

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From the Departments of Endocrinology and Metabolism.
System Biology, and.
Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641.
the Life Science Research Center, Kagawa University, Ikenobe 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793.
the Division of Natural System, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192.
the Department of Medical Life Systems, Faculty of Medical and Life Sciences, Systems Life Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394.
the Health Care Center, Kochi University, Kochi 780-8520.
the Department of Advanced Medicine, Kagawa University, Ikenobe 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, and.
PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
From the Departments of Endocrinology and Metabolism,


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.


diabetes; hepatocyte; insulin resistance; polyunsaturated fatty acid (PUFA); selenoprotein

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