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Session: Micronutrients, Supplements and Chronic Disease Mechanisms (Poster Theater Flash Session 12)

(PTFS12-02-23) Transcriptional Regulation of Elongase 3 by Selenium-Dependent Glutathione Peroxidase 1 in Mice Tissues

Tuesday, July 25, 2023
10:09 AM – 10:13 AM ET
Location:  Fairfax

    Presenting Author(s)

  • Ziqiao Sun, M.S.

    Ph.D. Candidate
    Cornell University
    Ithaca, New York, United States

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • KW

    Kun Wu

    South China Agricultural University

  • CF

    Chenhan Feng

    Cornell University

  • XL

    Xin Gen Lei, Ph.D.

    Professor
    Cornell University
    Ithaca, New York, United States

Disclosure(s):
Ziqiao Sun, M.S.: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: We have previously shown dysregulated lipid metabolism in tissues of mice overexpressing selenium-dependent glutathione peroxidase 1 (GPX1) (OE) or deficient in GPX1 (KO). This study aimed to explore the underlying mechanisms of GPX1 in regulating fatty acid (FA) metabolism in tissues of mice.

Methods: In Experiment 1, liver and adipose tissue were collected from the GPX1 OE, KO, and wild-type (WT) mice (n =5, male, 3-6 months) fed a Se-adequate diet (0.3 mg/kg) to assay for FA profiles and (or) gene expression of 11 transcriptional factors (TFs) related to lipid metabolism. In Experiment 2, the three genotypes of mice (n =5, male, 3-6 months) were injected intraperitoneally with diquat, ebselen, and N-acetylcysteine (NAC) at 10, 50, and 50 mg/kg body weight, respectively, and killed at 0, 6, and 12 h after the injections to detect mRNA levels of FA elongation-related genes and TFs in the liver and adipose tissue. In Experiment 3, transcriptional regulations of mouse elongase 3 (Elovl3, EC 2.3.1.199) by GPX1 mimic ebselen were determined using selected deletions of the gene promoter and a luciferase reporter assay in HEK293T cells.

Results: Compared with the WT, GPX1 OE and KO mice had 14-50% lower (P < 0.05) and 13-42% higher (P < 0.05) hepatic concentrations of C20:0, C22:0, and C24:0, respectively. These alterations were concurrent with down- or up-regulated (P < 0.05) Elovl3 and up- or down-regulated albumin D box-binding protein (Dbp) andspecificity protein 1 (Sp1), respectively. Compared with the controls, the Elovl3 mRNA abundance was decreased (12 h, P < 0.05) by ebselen and NAC, but elevated (12h, P < 0.05) by diquat (Dbp in the opposite direction). ELOVL3 level was diminished in the liver and adipose of OE mice but increased in KO mice. Three TFs (GABP, SP1, and DBP) were identified to bind the Elovl3 promoter region (-1164/0 base pair, bp). Deletion of DBP (-98/-86 bp) binding domain in the Elovl3 promoter attenuated (13%, P < 0.05) the inhibitory effect of ebselen on the Elovl3 promoter activation.

Conclusions: Hepatic concentrations of very long-chain fatty acids were inversely related to tissue levels of GPX1, and the negative effect of GPX1 was partially mediated by transcriptional inhibition of the Elovl3 promoter activation.

Funding Sources: Not available