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

Abstract

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.

Higher Serum Selenoprotein P Level as a Novel Inductor of Metabolic Complications in Psoriasis

“…There are also reports on the suppressing effect of metformin on selenoprotein P production in the liver, which contributes to the improvement of IR, however this was not investigated on human samples [ 56 , 57 ]. Tajima-Shirasaki N. et al presented that eicosapentaenoic acid (EPA), a component of ω-3 PUFAs (polyunsaturated fatty acids), inhibits SeP expression in rat hepatocytes [ 58 ]. Although, the data concern an animal model, they correlate with the wide literature data proving EPA deficiency in subjects with psoriasis and the beneficial effect of ω-3 PUFA supplementation on their clinical improvement [ 59 , 60 , 61 ].…”

Fatty acid elongase7 is regulated via SP1 and is involved in lipid accumulation in bovine mammary epithelial cells

“…It is evident that PUFAs not only maintain energy production throughout the body but also regulate the biological processes in cells. The recently published article demonstrated that eicosapentaenoic acid (EPA, 20:5n‐3) suppressed SELENOP gene expression by inactivating its transcriptional regulation (Tajima‐Shirasaki et al, ). In mammal, it has been identified that α‐linolenic acid (ALA, 18:3n‐3) is initially converted to stearidonic acid (SDA, 18: 4n‐3) by the Δ6‐desaturase (FADS2), and further is elongated and desaturated into EPA (Burdge & Calder, ).…”

Selenoprotein P as an <i>in vivo</i> redox regulator: disorders related to its deficiency and excess

“…In addition, eicosapentaenoic acid (EPA), a major component of w-3 polyunsaturated fatty acids (PUFAs) contained in fish oil, has been reported to decrease SeP expression in H4IIEC3 hepatocytes. (64)(65)(66) EPA is used to improve lipid metabolism and has beneficial effects in the treatment of type 2 diabetes. EPA has been known to activate AMPK; however, EPA decreases the binding of sterol regulatory element-binding protein-1c (SREBP-1c) to the SeP promoter region and lowers SeP levels.…”

“…Metformin and EPA decrease SeP mRNA expression. (61,64) However, these diabetes drugs are not effective against PAH-PASMC proliferation, which suggests other molecular mechanisms that increase SeP expression in PAH. (77) To inhibit the SeP expression in PAH-PASMCs, sanguinarine, a plant alkaloid, has been identified by highthroughput screening of 3,336 compounds.…”