Ablation of Selenbp1 Alters Lipid Metabolism via the Pparα Pathway in Mouse Kidney.

Yingxia Song,Junpei Mutoh,Yuko Onomura,Takayuki Koga,Atsushi Kurose,Yoshitaka Tanaka,Yuji Ishii,Renshi Li,Takumi Ishida,Tomoki Takeda

doi:10.3390/ijms22105334

Abstract

Selenium-binding protein 1 (Selenbp1) is a 2,3,7,8-tetrechlorodibenzo-p-dioxin inducible protein whose function is yet to be comprehensively elucidated. As the highly homologous isoform, Selenbp2, is expressed at low levels in the kidney, it is worthwhile comparing wild-type C57BL mice and Selenbp1-deficient mice under dioxin-free conditions. Accordingly, we conducted a mouse metabolomics analysis under non-dioxin-treated conditions. DNA microarray analysis was performed based on observed changes in lipid metabolism-related factors. The results showed fluctuations in the expression of numerous genes. Real-time RT-PCR confirmed the decreased expression levels of the cytochrome P450 4a (Cyp4a) subfamily, known to be involved in fatty acid ω- and ω-1 hydroxylation. Furthermore, peroxisome proliferator-activated receptor-α (Pparα) and retinoid-X-receptor-α (Rxrα), which form a heterodimer with Pparα to promote gene expression, were simultaneously reduced. This indicated that reduced Cyp4a expression was mediated via decreased Pparα and Rxrα. In line with this finding, increased levels of leukotrienes and prostaglandins were detected. Conversely, decreased hydrogen peroxide levels and reduced superoxide dismutase (SOD) activity supported the suppression of the renal expression of Sod1 and Sod2 in Selenbp1-deficient mice. Therefore, we infer that ablation of Selenbp1 elicits oxidative stress caused by increased levels of superoxide anions, which alters lipid metabolism via the Pparα pathway.

Highlights

Selenium is an essential trace element that is incorporated into selenoproteins as selenocysteine to mediate its functions
Dioxin migrates into the nucleus by binding to the aryl hydrocarbon receptor (AhR), which is localized in the cytosol, forms a heterodimer with the nuclear translocator (Arnt) [21], and binds to a xenobiotic responsive element (XRE) [22]
We evaluated the role of Selenbp1 in the kidney, as Selenbp2 is barely expressed in the kidney

Summary

Introduction

Selenium is an essential trace element that is incorporated into selenoproteins as selenocysteine to mediate its functions. Selenium-binding protein 1 (Selenbp1) is a highly conserved and unconventional selenoprotein with distinct (perselenide) or undetermined selenium chemistry [5]. It was first discovered in the mouse liver [6]. As the kidney level of Selenbp is low [18], we aimed to clarify the role of dioxin-inducible Selenbp in the kidney by eliminating other factors altered by dioxin. To address this issue, we performed metabolomic and DNA microarray analyses of the kidneys to examine the effect of Selenbp ablation. Based on the observed results, it can be suggested that ablation of Selenbp alters the lipid metabolism via downregulation of peroxisome proliferator-activated receptor-α (Pparα (Ppara))

Objectives

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Results

Conclusion