Effect of statin treatment in obese selenium-supplemented mice lacking selenocysteine lyase

Abstract

People with obesity are often dyslipidemic and prescribed statins to prevent cardiovascular events. A common side effect of statin use is myopathy. This could potentially be caused by the reduction of selenoproteins that curb oxidative stress, in turn, affecting creatine metabolism. We determined if statins regulate hepatic and muscular selenoprotein expression, oxidative stress and creatine metabolism. Mice lacking selenocysteine lyase (Scly KO), a selenium-provider enzyme for selenoprotein synthesis, were fed a high-fat, Se-supplemented diet and treated with simvastatin. Statin improved creatine metabolism in females and oxidative responses in both sexes. Male Scly KO mice were heavier than females after statin treatment. Hepatic selenoproteins were unaffected by statin and genotype in females. Statin upregulated muscular Gpx1 in females but not males, while Scly loss downregulated muscular Gpx1 in males and Selenon in females. Osgin1 was reduced in statin-treated Scly KO males after AmpliSeq analysis. These results refine our understanding of the sex-dependent role of selenium in statin responses.

Keywords: Obesity; Selenium; Selenocysteine lyase; Statin.

Figure 1:

Treatment protocol.

Figure 2:. Hepatic squalene synthase (SQS) expression measured by Western blot and normalized by expression levels of β-actin.

n = 3–4 per group. Two-way ANOVA was applied, considering the differences between treatments (VTM × STM) and/or between genotypes (WT × KO), for males and females separately, and P values are displayed in the inset table. VTM: vehicle-treated mice; STM: statin-treated mice; WT: wild type; KO: knockout.

Figure 3:. Body and adipose depot weights in male (A–C) and (D–F) female WT and Scly KO mice.

Body weights from male (A) and female (D) mice from 3 to 12 weeks of age were monitored biweekly. Male white gonadal (B) and brown adipose tissue (C), and female white gonadal (E) and brown adipose tissue (F) weights were measured after the end of experiment. Values are mean + SEM and in (B), (C), (E), and (F) were normalized by total body weight at 12 weeks for each mouse. Two-way ANOVA was applied, followed by Bonferroni’s post-hoc test, considering the differences between treatments (VTM × STM) and/or between genotypes (WT × Scly KO), for males and females separately. *, P < 0.05; **, P < 0.01; ***, P < 0.001, n=9–11 per genotype. gWAT, gonadal white adipose tissue; BAT, brown adipose tissue, VTM: vehicle-treated mice; STM: statin-treated mice; WT: wild type; KO: knockout. Black bars, WT; gray bars, Scly KO.

Figure 4:. Hepatic protein levels in male (A–E) and female (F–J) mice.

Levels of (A, F) NGAL, (B, G) Osgin1, (C, H) Camk2b, (D, I) CYP3a4, (E, J) Igfbp2 were assessed by Western Blot, with results normalized by the expression of β-actin. Data are mean ± SEM. Two-way ANOVA (2WA) was performed and *, ** and *** represent P<0.05, P<0.01, and P<0.001 respectively, after Bonferroni’s post-test; n=4 per group. Black bars, WT; gray bars, Scly KO.