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. Author manuscript; available in PMC: 2026 Jun 18.
Published in final edited form as: J Trace Elem Med Biol. 2025 Jun 18;90:127685. doi: 10.1016/j.jtemb.2025.127685

A SELENOMETHIONINE DEFICIENT, HIGH-FRUCTOSE DIET DOES NOT LEAD TO CARDIOMETABOLIC DISORDER IN THE SELENOCYSTEINE LYASE KNOCKOUT MICE

BK Shimada 1, NK Apo Takayama 1, KA Hallam 1, PJD Santiago 1, JY Yew 1, N Alfulaij 1, K Nakahara-Akita 1, AG Soares 1, MJ Berry 1, LA Seale 1
PMCID: PMC12367225  NIHMSID: NIHMS2092060  PMID: 40543467

Abstract

Background/Purpose:

High-fructose consumption is a driver of cardiometabolic disorders and metabolic syndrome, and selenium (Se) deficiency further increases the risk of developing these diseases. Consuming high amounts of fructose induces insulin resistance and oxidative stress, and alters the cardiac lipidome. Se may reduce the detrimental impacts of fructose through its incorporation into selenoproteins like the glutathione peroxidases 1 and 4, (GPX1,4) and the thioredoxin reductase 1 (TXNRD1) whose primary function is to curb oxidative stress. When Se levels are limited, selenocysteine lyase (SCLY) decomposes selenocysteine (Sec) to hydrogen selenide (H2Se), and loss of Scly results in metabolic syndrome in mice. However, it is unknown if SCLY is required to sustain the synthesis of critical antioxidant selenoproteins to prevent oxidative stress, cardiometabolic disorders, and metabolic syndrome caused by high-fructose consumption.

Methods:

In this study, we analyzed cardiometabolic parameters, the cardiac lipidome, and the cardiac protein levels of GPX and TXNRD in male and female whole-body Scly knockout (Scly KO) mice fed a selenomethionine (SeMet) deficient, high-fructose diet.

Results/Conclusion:

We found that selenomethionine deficiency, coupled with high-fructose consumption does not lead to cardiometabolic disorder in the Scly KO mice, and suggests that there are compensatory mechanisms involving Se metabolism that are protective against fructose-induced cardiometabolic disorder.

Keywords: Fructose, selenium deficiency, selenocysteine lyase, cardiometabolic disorder

INTRODUCTION

High-fructose consumption drives cardiometabolic disorders such as type 2 diabetes (T2D) and metabolic syndrome1,2. Excessive dietary fructose induces insulin resistance and oxidative stress, and increases cardiac lipid species such as triacylglycerols and diacylglycerols3 that are associated with cardiovascular diseases (CVDs)4,5. Selenium (Se), through its incorporation into selenoproteins that reduce oxidative stress, may counteract the effects of high-fructose consumption. Se maintains cellular redox homeostasis by controlling the levels of selenoproteins, such as glutathione peroxidases 1 and 4 (GPX1 and GPX4) and thioredoxin reductase 1 (TXNRD1), that curb reactive oxygen species (ROS). When Se levels are low, selenocysteine lyase (SCLY) decomposes and recycles selenocysteine (Sec) to hydrogen selenide (H2Se), which is the metabolite used to synthesize selenoproteins6. This process becomes particularly critical when Se levels are deficient. Loss of Scly accompanied by dietary Se deficiency results in metabolic syndrome in mice7, a disorder that can also be caused by elevated fructose consumption8–10, and may lead to CVDs.

In the heart, fructose alters the lipidome11 and increases cell death12 and reactive oxygen species (ROS)13. By controlling the levels of antioxidant selenoproteins such as GPX1, GPX4, and TXNRD1, Se curbs ROS induced by fructose consumption. GPX1 and GPX4 decrease the damage caused by ROS14, and TXNRD1 regulates intracellular redox reactions to protect cells from oxidative stress15,16. Specifically, GPX1 regulates hydrogen peroxide detoxification and is sensitive to Se levels, while GPX4 reduces toxic phospholipid hydroperoxides. Notably, mice lacking Gpx1 exhibit increased damage after ischemia-reperfusion (I/R) injury17. TXNRD1 regulates intracellular redox reactions by using NADPH/H+ to regenerate thioredoxins and reduce oxidized cysteine residues in cellular proteins15,16. TXNRDs also play vital roles in cardiac injury as they alleviate oxidative stress due to pressure overload-induced hypertrophy18 and minimize left ventricular remodeling15. Therefore, maintaining the expression of selenoproteins such as the GPXs and the TXNRDs in the heart to curb ROS may be beneficial, particularly under Se deficiency.

It is unknown if SCLY is required to sustain the synthesis of the critical antioxidant selenoproteins GPX1, GPX4, and TXNRD1 in the heart, preventing oxidative stress and cardiometabolic disorders caused by high-fructose consumption. We hypothesize that loss of Scly accompanied by Se deficiency and a high-fructose diet leads to cardiometabolic disorder by increasing oxidative stress and altering the cardiac lipidome. As overconsumption of fructose and Se deficiency are both associated with the development of T2D in humans1,2,19, we investigated whether Se deficiency and a high-fructose diet led to the development of cardiometabolic disorder.

In this study, we used selenomethionine (SeMet) as the dietary source of Se at low concentrations in combination with a high-fructose or a high-dextrose diet to determine if a low SeMet, high-fructose diet can lead to the development of cardiometabolic disorders upon loss of Scly in mice. We placed both non-littermate WT and Scly KO and littermate control (CON) and Scly−/− mice on these diets and found that, while selenoprotein GPX1 was significantly reduced in the hearts of both male and female Scly KO mice on a low SeMet, high-fructose diet, there was no development of cardiometabolic disorder in either non-littermate Scly KO or littermate Scly−/− mice. This suggests that in the heart, Scly controls GPX1 levels in response to a high-fructose diet as the synthesis of the other selenoproteins were sustained in the absence of Scly. Therefore, this may explain why the Scly KO mice did not develop cardiometabolic disorder as the other selenoproteins compensated for the decrease in GPX1.

METHODS

Chemicals and antibodies.

Unless specified, all chemicals used in experiments were purchased from Fisher Scientific (Waltham, MA), Cell Signaling Technology (Danvers, MA), or Sigma-Aldrich (St. Louis, MO). Antibodies used in assays, their vendors and concentrations are presented in Supplemental Table 1.

Animals.

All animal procedures were approved by the University of Hawaii Institutional Animal Care and Use Committee (IACUC) protocol #22–3723. Mice were used for experiments in minimal numbers as calculated by power analysis from the University of British Columbia, Canada (online tool) where mu1=0.97, mu2=0.95 with a sigma = 0.12, and 80% power to provide significant results. Mice with a whole-body deletion of the Scly gene (Scly KO) have been previously described, and both Scly KO and wild-type (WT) mice were on a C57BL6/N background20. Littermate control (CON) and Scly KO (Scly−/−) and non-littermate WT and Scly KO mice were used to prevent background genetic differences from influencing results and both male and female mice were used. Mice were group housed and placed on a 12h/12h day/light cycle at room temperature and were fed ad libitum customized high-fructose (60%) or high-dextrose (60%) diets containing 0.08 ppm selenomethionine (SeMet) (Inotiv, West Lafayette, IN) for 8 weeks starting at weaning age. See Supplemental Data for the formulation of the high-fructose and high-dextrose diets. We used SeMet as the dietary source of Se as it requires SCLY to be fully metabolized into Sec in the last step of the trans-selenation pathway, whereas selenite is processed into selenide by a SCLY-independent mechanism21. Euthanasia was carried out by avertin (250 mg/kg) intraperitoneal injection, and extracted hearts were snap-frozen in liquid nitrogen.

Serum leptin assay.

A commercially available ELISA colorimetric kit was used to assay for leptin (Catalog No: #90030, antibody RRID: AB_2722664; Crystal Chem, Elk Grove Village, IL) with 5 μl of sample. Intra-assay coefficient of variance remained < 5%. Absorbance at 630 nm was subtracted from absorbance at 450 nm, and leptin concentration was calculated based on a standard curve provided by the kit.

Glucose tolerance test.

Mice were fasted overnight for 16 hours. A baseline fasting blood glucose measurement (prior to glucose injection) was taken using a OneTouch Ultra 2 meter. Following the baseline measurement, then the mice were injected with a bolus of glucose (1.0 g glucose/kg body weight) dissolved in sterile water. Blood glucose measurements were then recorded at 0.5, 1-, 2-, and 3-hours post-glucose injection. Blood glucose was measured at 3 hours to observe whether glucose levels returned to baseline levels.

Insulin tolerance test.

Mice were fasted for 4 hours. A baseline blood glucose measurement (prior to insulin injection) was taken, and then mice were injected with 0.75 Units/kg of insulin dissolved in sterile water. Blood glucose measurements were then recorded at 0.5, 1-, and 2-hours post-injection.

Serum collection.

Serum was collected from avertin (250 mg/kg, intraperitoneal injection) anesthetized mice via cardiac puncture and a 26½ gauge needle. Blood was allowed to clot at room temperature for 15–30 minutes. Blood was then centrifuged at 2000 × g for 10 minutes, and the serum was collected and stored at −80°C until analysis.

Echocardiography.

Echocardiography was performed on non-anesthetized mice using an MS400 transducer (Vevo 2100 Imaging system, Visual Sonics, Toronto, ON, Canada) after 8 weeks on customized diets. M-mode images used for measurements were taken at the papillary muscle level and quantified for percent fractional shortening (%FS), left ventricular internal dimension diastole (LVIDd), and left ventricular internal dimension systole (LVIDs). M-mode data was analyzed with Vevo 2100 software (version 1.0).

Fatty acid analysis.

Heart tissue was weighed and placed in 2 mL tubes. They were homogenized in 100 μL MilliQ water using ceramic beads and 20 μL was set aside for protein quantification. Lipids were extracted using a chloroform (CHCl3)/ methanol (MeOH) mixture at a 2:1 ratio and spiked with 10 μg/mL pentadecanoic acid for use as an internal standard. Samples were then shaken at 4°C for three hours. A 44% MeOH/water solution was then added to samples and the lower phase was collected and transferred to a 2 mL glass vial. The lipids were re-extracted twice with 400 uLCHCl3 and each time centrifuged at 7,500 × g at 4°C. Following the last centrifugation step, the contents of the glass vial were dried using nitrogen gas and samples were stored at −20°C. Samples were esterified by incubating samples in 0.5N methanolic HCl in a water bath at 65°C for 1.5 hours with occasional vortexing. Following incubation, the solvent was evaporated nitrogen gas and the sample was reconstituted in 1000 μL hexane for analysis.

Gas chromatography mass spectrometry (GCMS):

GCMS analysis was performed on a 7820A GC system equipped with a 5975 Mass Selective Detector (Agilent Technologies, Inc., Santa Clara, CA, USA) and an HP-5ms column ((5%-Phenyl)-methylpolysiloxane, 30 m length, 250 μm ID, 0.25 μm film thickness; Agilent Technologies, Inc.). Electron ionization (EI) energy was set at 70 eV. One μL of the sample was injected in splitless mode and analyzed with helium flow at 1 mL/ min. For fatty acids, the oven was initially set at 50 °C for 2 min, increased to 90 °C at a rate of 20 °C/min and held at 90 °C for 1 min, increased to 280 °C at a rate of 5 °C/min and held at 280 °C for 2 mi. The MS was set to detect from m/z 33 to 500 and data were analyzed using MSD ChemStation v. D.03.00.611 (Agilent Technologies, Inc.). The FAs were identified based on retention time and electron ionization fragmentation pattern. The abundance of each compound was quantified by normalizing the area under each CHC peak to the area of the hexacosane signal.

Western Blot.

Heart protein was extracted using RIPA lysis buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS, Catalog No: 89901, ThermoFisher Scientific, containing 1X protease and phosphatase inhibitor (Catalog No: 5872, Cell Signaling Technology). 10–20 μg of total protein was loaded into 4–20% SDS-PAGE and transferred overnight to an Immobilon-FL® membrane (Catalog No: IPFL00010, Millipore-Sigma; Burlington, MA) in a wet or semi-dry transfer assembly of tris-glycine buffer with 9% methanol. Primary antibodies were incubated overnight at 4°C with rotation while infrared labeled secondary antibodies were incubated for 1 hour at room temperature with rotation. Blots were imaged using a Li-Cor Odyssey Fc image infrared scanner (Li-Cor; Lincoln, NE). Primary and secondary antibodies used in our study are listed in Supplemental Table 1.

RNA extraction and real-time qPCR.

Total RNA from the liver and kidney was extracted using Omega Biotek’s E.Z.N.A. Total RNA kit (Catalog No: R6834–02, Norcross, GA). One μg of total RNA was then reverse transcribed using the High-Capacity kit (Applied Biosystems – ThermoFisher Scientific, Waltham, MA). 10 ng of cDNA were used in real-time qPCR reactions for selected genes using specific primers, listed in Supplemental Table 2. qPCR reactions were carried out using the PerfeCTa SYBR Green SuperMix (Quantabio; Beverly, MA) and run on a Roche LightCycler 480 II (Indianapolis, IN) following MIQE guidelines22,23. Calculations were performed using the Δ−Ct method after appropriate melting curves were generated, normalized by the expression of reference genes Gapdh, 18S, and Actb, and plotted as fold change.

Statistical Analysis.

Statistical analysis was performed using GraphPad Prism 9 software (RRID:SCR_002798, GraphPad, La Jolla, CA). Unless stated otherwise, the distributions of the continuous variables were expressed as the mean ± SEM. D’Agostino and Pearson (single comparison) or Kruskal-Wallis (multiple comparisons) normality tests were used to evaluate the normality of the data. If normal, the statistical significance of the difference between groups was measured by two-tailed t-test with Welch’s correction, one-way ANOVA with Tukey’s post hoc test for one variable or two-way ANOVA with Bonferroni’s post hoc test for two variables. If the data did not pass the normality test, non-parametric tests (Mann-Whitney) for single comparisons were used to derive the P values. The null hypothesis was rejected for P < 0.05 with the statistical tests.

RESULTS

Selenium deficiency and a high-fructose diet does not result in cardiometabolic disorder

To determine if SCLY mitigates the detrimental effects of a high-fructose diet on cardiometabolic disorder, we placed both non-littermates (WT vs Scly KO) and littermate (control, CON vs. Scly−/−) mice of both sexes on a low SeMet, high-fructose or high-dextrose diet as diagrammed in Fig. 1A for 8 weeks starting at weaning age. We found that the body weight was similar between non-littermate WT and Scly KO and littermate CON and Scly−/− mice (Fig. 1B–E) on both a low SeMet, high-fructose or a low SeMet, high-dextrose diet. Although body weight was similar between non-littermate WT and Scly KO and littermate CON and Scly−/− mice on both a low SeMet, high fructose and high dextrose diet, leptin was significantly increased in the serum of female Scly KO mice on a low SeMet high fructose diet (7.76 ± 0.88 vs. 18.73 ± 4.63 ng/mL, WT vs Scly KO, P < 0.01, Fig. 1F). Despite elevated leptin, other indicators of overweight/obesity, such as inguinal white adipose tissue (iWAT) weight-to-body weight ratio, remained similar between both WT and Scly KO and CON and Scly−/− mice on either diet (Fig. 2A). Other indicators of cardiometabolic syndrome such as liver weight to body weight ratio and heart weight to tibia length ratio were also similar across all groups although there was a trend towards a slight increase in heart weight to tibia length ratio between littermate CON and Scly−/− male mice (0.046 ± 0.014 vs. 0.060 ± 0.009 a.u., CON vs Scly−/−, P = 0.06, Fig. 2F).

Figure 1. High-fructose and Se deficiency on body weight in mice lacking Scly.

Figure 1.

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Non-littermate WT and Scly KO and littermate CON and Scly−/− were administered either a 0.08 ppm SeMet, high-fructose or a 0.08 ppm SeMet, high-dextrose diet for 8 weeks starting at weaning age. Body weight was tracked each week for 8 weeks. A. Schematic of the experimental timeline. B-C. Graph of body weight change of non-littermate and littermate mice on a 0.08 ppm SeMet, high-fructose diet. D-E. Graph of body weight change of non-littermate and littermate mice on a 0.08 ppm SeMet, high-dextrose diet. F. Leptin levels in combined non-littermate and littermate mice on a 0.08 ppm SeMet, high-fructose and high-dextrose diet. Each error bar represents mean ± SEM, n values displayed on graphs. Data in all graphs were analyzed using a mixed-effects analysis. **P < 0.05, **P < 0.01, ****P< 0.0001. CON, littermate control; Scly−/−, littermate Scly KO; SeMet, selenomethionine.

Figure 2. Organ weights of Scly KO mice fed a high-fructose, Se-deficient diet.

Figure 2.

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After 8 weeks of either 0.08 ppm SeMet, high-fructose or high-dextrose diet, liver, iWAT, and hearts from non-littermate WT and Scly KO and littermate CON and Scly−/− were collected and weighed. Liver and iWAT were normalized to body weight, and heart weight was normalized to tibia length. A-B. iWAT to BW ratio. C-D. Liver to BW ratio. E-F. Heart weight to TB ratio. Each error bar represents mean ± SEM, n values displayed on graphs as dots. Data in all graphs were analyzed with a two-tailed t-test with Welch’s correction. Graphs are plotted together for visualization purposes. BW, body weight; TB, tibia length; iWAT, inguinal white adipose tissue.

To further verify that increased fructose consumption does not lead to cardiometabolic disorder, we also performed glucose and insulin tolerance tests. Again, there was no difference in glucose tolerance between non-littermate WT and Scly KO and littermate CON and Scly−/− when mice were on either a low SeMet high-fructose or a high-dextrose diet as area under the curve (AUC) was similar across all groups. This was also mostly similar for the insulin tolerance test in mice administered either a low SeMet, high-fructose or a low SeMet, high-dextrose diet except in non-littermate WT and Scly KO mice. We found that WT males exhibited slightly more insulin resistance than their Scly KO counterparts when WT and Scly KO mice were given a high-dextrose diet. However, there was no difference in littermate CON and Scly−/− mice. This indicates that high-fructose consumption combined with selenium deficiency does not induce glucose intolerance or insulin resistance in mice lacking Scly.

Selenium deficiency combined with a high-fructose diet does not result in cardiac dysfunction

We next checked cardiac function of the mice, as a high-fructose diet is known to induce cardiac dysfunction24. As both metabolic parameters and heart weight to tibia length ratio were similar between non-littermate and littermates, indicating no cardiac hypertrophy in any of the groups, we analyzed the cardiac function in only the non-littermate WT and Scly KO mice. We found that percent fractional shortening (%FS), left ventricular interior diameter diastole (LVIDd), and left ventricular interior diameter systole (LVIDs) were all similar between both male and female WT and Scly KO mice on either a low SeMet, high-fructose or high-dextrose diet (Fig. 4A–F) therefore indicating that Se deficiency in combination with a high-fructose diet does not impact cardiovascular function.

Figure 4. Echocardiographic parameters in mice lacking Scly on a high-fructose or high-dextrose diet.

Figure 4.

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WT and Scly KO male and female mice were placed on an either a 0.08 ppm SeMet, high-fructose or high-dextrose diet for 8 weeks. Just prior to termination, echocardiography was performed. A-B. %FS in male and female WT and Scly KO mice on either a high-fructose or high-dextrose diet. C-D. LVIDd in male and female WT and Scly KO mice. E-F. LVIDs in male and female WT and Scly KO mice. Each error bar represents mean ± SEM, n values displayed on graphs as dots. All graphs were analyzed with a two-tailed t-test with Welch’s correction. %FS, percent fractional shortening; LVIDd, left ventricular interior diameter diastole; LVIDs, left ventricular interior diameter systole.

The combination of loss of Scly, selenium deficiency, and a high-fructose diet does not alter cardiac fatty acid species

High-fructose consumption is known to alter fatty acid species in the heart11,25. We, therefore, determined if there were differences in fatty acid species in the heart using fatty acid analysis. Again, since metabolic parameters between both non-littermate WT and Scly KO and littermate CON and Scly−/− on high-fructose diets were similar to each other, we only assessed the cardiac fatty acid content of non-littermate WT and Scly KO mice. Fatty acid analysis demonstrated that there were no differences in the levels of any of the 15 fatty acid species we assessed between WT and Scly KO mice in both males and females (Fig. 5A–B). Furthermore, total fatty acids and branched-chain fatty acids were also the same levels between both male and female WT and Scly KO mice (Fig. 5C–D). Therefore, loss of Scly does not impact fatty acid species in the hearts of mice on a selenium-deficient, high-fructose diet.

Figure 5. Fatty acid analysis of hearts from Scly KO mice on a low SeMet, high-fructose diet.

Figure 5.

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After 8 weeks of a low SeMet, high-fructose diet, hearts from WT or Scly KO mice were analyzed using fatty acid analysis. A-B. Relative abundance of fatty acids in either WT or Scly KO male or female hearts. C-D. Quantification of the total amount of fatty acids in the heart from either WT or Scly KO male or female hearts. n values displayed on graphs as dots. Data was analyzed with a two-tailed t-test with Welch’s correction. FA, fatty acid; BCA, branch chain acid.

Selenoprotein GPX1 is significantly decreased in the hearts of Scly KO mice on a selenium deficient, high-fructose diet

Then, to determine if Scly does control the level of selenoproteins known to execute antioxidant function in the heart, we assessed the protein levels of GPX1, GPX4, and TXNRD1 in the hearts of WT and Scly KO mice on a low SeMet, high-fructose diet. We found that GPX1 was significantly decreased in the hearts of female Scly KO mice (0.688 ± 0.27 vs 0.087 ± 0.07, WT vs. Scly KO, n = 6, P < 0.01) and also trended down in male hearts (0.554 ± 0.16 vs 0.148 ± 0.02 a.u., WT vs. Scly KO, n = 6, P = 0.055) (Fig. 6A–B). GPX4 and TXNRD1 protein levels were similar between WT and Scly KO mice in both males and females (Fig. 6A–C). This suggests that loss of Scly and Se deficiency impacts only GPX1 but not the expression of other selenoproteins, such as GPX4 and TXNRD1, at least in the heart.

Figure 6. Selenoproteins in Scly KO mice hearts on a low SeMet, high-fructose diet.

Figure 6.

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A-B. Representative western blot of GPX1 and GPX4 protein in either male or female WT and Scly KO hearts and quantification. C-D. Representative western blot of TXNRD1 protein in either male or female WT and Scly KO mice and quantification. Each error bar represents mean ± SEM, n values displayed on graphs as dots. All graphs were analyzed with a two-tailed t-test with Welch’s correction.

Cystathionine gamma lyase levels are increased in the hearts of Scly KO mice on a selenium deficient, high fructose diet

As GPX1 was the only selenoprotein found to be decreased in the hearts of Scly KO mice on a low SeMet, high fructose diet, we next assessed the Se metabolism enzymes cystathionine beta synthase (CBS), cystathionine gamma lyase (CGL), and selenophosphate synthetase 2 (SEPHS2) in the hearts of our Scly KO mice on a low SeMet, high fructose diet. In female hearts, there was no difference in CBS, CGL, or SEPHS2 between WT and Scly KO mice (0.118 ± 0.05 vs. 0.626 ± 0.25, WT vs Scly KO, n = 6, P < 0.05, Fig. 7A–C). However, in male hearts we observed an increase in CGL (Fig. 7B) while CBS and SEPHS2 were unaffected (Fig. 7A and C). This result shows male and females may have different Se metabolism mechanisms to compensate for the loss of Scly.

Figure 7. Selenium metabolism proteins in Scly KO mice hearts on a low SeMet, high-fructose diet.

Figure 7.

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A-C. Representative western blot of CBS, CGL, and SEPHS2 proteins in male or female WT and Scly KO hearts and quantification. Each error bar represents mean ± SEM, n values displayed on graphs as dots. All graphs were analyzed with a two-tailed t-test with Welch’s correction except the graphs in B titled CGL - Protein (M) Heart and C titled SEPHS2 - Protein (F) Heart, which did not pass the normality test and were analyzed with the Mann-Whitney test. *P < 0.05.

Selenoprotein expression in the kidney and liver largely remains unchanged in Scly KO mice on a selenium deficient, high fructose diet.

Finally, to evaluate whether other tissues may have altered selenoprotein levels, we checked the liver for GPX1, GPX4, TXNRD1, and SEPHS2 from WT and Scly KO mice on a low SeMet, high fructose diet. TXNRD1 and GPX1 protein levels were unchanged in both male and female Scly KO mice on a low SeMet, high fructose diet (Fig. 8A–B). GPX4 was significantly decreased in male Scly KO livers (0.748 ± 0.02 vs. 0.577 ± 0.04 a.u., WT vs Scly KO, P < 0.05), but not in female Scly KO livers (Fig. 8C). Meanwhile, SEPHS2 was significantly decreased in female Scly KO livers (0.920 ± 012 vs. 0.504 ± 0.01 a.u., WT vs Scly KO, P <0.05), but not in male Scly KO livers (Fig. 8D). There was no difference in any of the following selenoprotein gene transcripts that we analyzed in the liver: Selenop, Gpx1, Gpx4, Txnrd1, Dio1, Selenow, and Msrb1, although Msrb1 gene transcripts trended towards being increased in female Scly KO livers (P = 0.055, Fig. 8E).

Figure 8. Selenoproteins in Scly KO mice livers on a low SeMet, high-fructose diet.

Figure 8.

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A-B. Representative western blot of TXNRD1 and GPX1 protein in male or female WT and Scly KO livers and quantification. C. Representative western blot of GPX4 protein in male or female WT and Scly KO livers and quantification. D. Representative western blot of SEPHS2 protein in male or female WT and Scly KO livers and quantification. E. qPCR analysis of Selenop, Gpx1, Gpx4, Txnrd1, Dio1, Selenow, and Msrb1 in the liver of WT and Scly KO mice on a 0.08 ppm SeMet, high fructose diet. Each error bar represents mean ± SEM, n values displayed on graphs as dots. All graphs were analyzed with a two-tailed t-test with Welch’s correction except for the graph in D titled SEPHS2 - Protein (F) Liver which did not pass the Normality test and was analyzed with the Mann-Whitney test. *P < 0.05. HK, housekeeping genes.

In the kidneys, GPX3 protein levels were unchanged in both male and female Scly KO mice on a low SeMet, high fructose diet (Fig. 9A). On a gene level, Gpx3 and Gpx4 gene transcripts were significantly decreased, while Gpx1 and Selenop trended down in female Scly KO kidneys (P = 0.09 and P = 0.10 respectively, Fig. 9B). In male kidneys, only Selenop gene transcripts were decreased, although Gpx1 trended towards being decreased (P = 0.16), and Gpx3 trended towards upregulation (P = 0.06, Fig. 9B). This data shows that although selenoprotein gene transcripts were affected by the loss of Scly and a low SeMet, high fructose diet, protein expression of these selenoproteins remained largely unaffected in both the liver and kidneys.

Figure 9. Selenoproteins in Scly KO mice kidneys on a low SeMet, high-fructose diet.

Figure 9.

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A-B. Representative western blot of GPX3 protein in male or female WT and Scly KO kidneys and quantification. B. qPCR analysis of Selenop, Gpx1, Gpx3, and Gpx4 in the kidneys of WT and Scly KO mice on a 0.08 ppm SeMet, high fructose diet. Each error bar represents mean ± SEM, n values displayed on graphs as dots. All graphs were analyzed with a two-tailed t-test with Welch’s correction. *P < 0.05. HK, housekeeping genes.

DISCUSSION

We found that the genetic deletion of Scly, which encodes for the protein that decomposes the amino acid Sec, combined with Se deficiency and a high-fructose diet does not lead to the development of cardiometabolic disorder. Although GPX1 protein levels in the heart are significantly impacted by the loss of Scly, the other antioxidant selenoproteins GPX4 and TXNRD1 were sustained, indicating that these selenoproteins may functionally compensate for the reduction in GPX1 expression. This suggests that the metabolism of fructose may be independent of Se metabolism. Most studies have focused on Se supplementation to reduce the detrimental effects of high-fructose consumption26–28, and have not analyzed whether there is an interaction between Se metabolism and fructose.

Notably, a diet high in fructose and low in Se did not lead to any metabolic disturbances in WT or Scly KO mice. Increased liver weight and iWAT are indicators of obesity as fat accumulates in both organs when mice are administered obesogenic diets; however, liver weight and iWAT weight were similar between both non-littermate WT and Scly KO and littermate CON and Scly−/− mice. Additionally, other indicators of metabolic dysfunction, such as glucose tolerance and insulin tolerance, were also similar across all groups. This is unexpected for two reasons. The first reason is because leptin levels were found to be increased in Scly KO female on a low SeMet, high fructose diet and high leptin levels are associated with obesity29. We showed that, when fed a high-fat, adequate selenite diet, which is also obesogenic, Scly KO mice showed elevated circulating leptin30, yet this was accompanied of exacerbated obesity and several metabolic issues. Secondly, previous studies by our laboratory demonstrated that both a regular chow diet and a high-fat diet led to metabolic syndrome, especially when Se levels are deficient, as indicated by the development of glucose intolerance, insulin resistance, fatty liver, and hypercholesterolemia7,31. That same study also showed that the regular chow diet elevated several pro-lipogenic markers in the liver of Scly KO mice, including peroxisome proliferator-activated receptor gamma and alpha, and acetyl coenzyme A carboxylase 17. However, in our current study, we did not find any evidence of metabolic disturbances.

The discrepancy between previous studies and this report may be explained by the chemical form of Se present in the diet. Selenite or a mixture of selenite and SeMet were the dietary source of Se in the previous studies30 31. Selenite and SeMet are metabolized by separate pathways. SeMet is metabolized by SCLY into Sec in the last step of the trans-selenation pathway, whereas selenite is processed into selenide by a reduction reaction that is SCLY-independent 21. Notably, in this study, we exclusively used SeMet as a dietary source of Se. In addition, Selenite and SeMet are absorbed by the body differently; in humans, selenite is absorbed at a rate of about 34–47% of ingested selenite compared to 96% of ingested SeMet32 and the absorption characteristics are likely similar in mice. Therefore, the chemical source of Se is a determinant in the development of cardiometabolic issues as SeMet is more bioavailable compared with selenite. Studies on the gut microbiota support this as both inorganic and organic selenocompounds are metabolized to SeMet and incorporated into bacterial proteins to serve as a Se reservoir for the host33. Additionally, in plants, SeMet can be mis-incorporated in the place of methionine in normal proteins, a process that has been assumed to also occur in mammals34. Therefore, SeMet can be stored in non-selenoproteins, serving as a reservoir of Se where SeMet can then be metabolized to Sec through the trans-selenation pathway by the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CGL)21. Alternatively, there may have also been compensatory enzymatic pathways in the microbiome that may have arisen as a result of the long-term fructose diet. While there were no differences in the Se metabolism proteins CBS, CGL, and SEPHS2 in the hearts of females lacking Scly, it does not preclude that Se metabolism is unaffected in the microbiome. Either the Se reservoir or another compensatory mechanism may explain why there are fewer differences between WT and Scly KO when using SeMet as the dietary source of Se because the expression of selenoproteins may be better maintained while using SeMet, despite the loss of Scly. Indeed, this is supported by a previous study showing that a supplemental dose of SeMet of 37 μg/day is sufficient to raise human GPX plasma levels to a maximum of 150 U/L, while 66 μg/day of selenite is needed to achieve this same level35. The higher bioavailability of SeMet may explain why decreases in selenoprotein expression were minimal compared with our previous studies, which used selenite as the primary dietary source of Se, and why there were no cardiometabolic effects in this study as selenoprotein expression could be maintained. This is supported by our data that shows GPX4 and TXNRD1 expression is maintained in the hearts of both male and female Scly KO mice as well as our data of the selenoproteins in the liver and kidneys. Although SEPHS2 protein levels were decreased in the livers of female Scly KO mice on a low SeMet, high fructose diet, this reduction did not impact other selenoproteins, again pointing to the possibility of a Se reservoir or a compensatory mechanism in the microbiome to help the Se supply. These possibilities are supported by the observed increase in CGL in the heart in males, and again point to the characteristic sexual dimorphism in Se metabolism that has already been thoroughly described31,36,37.

An alternative explanation for the maintenance of selenoprotein synthesis in Scly KO mice on a low Se, high-fructose diet is that another mechanism exists for metabolizing Sec. This possibility has been raised by recent studies suggesting that selenide may be delivered to the selenoprotein biosynthesis machinery by peroxiredoxin 6 (PRDX6)38–40. PRDX6 can react with selenide and interacts with selenophosphate synthetase 2 (SEPHS2), the enzyme that catalyzes the delivery of selenide into the monoselenophosphate intermediate that is needed for selenoprotein synthesis. The increased bioavailability of SeMet versus selenite and as well as this alternative pathway for the metabolism of Sec may help explain why we did not see any cardiometabolic impacts with high-fructose consumption in our Se-deficient, Scly KO mice.

Although excessive fructose consumption has been demonstrated to induce cardiac dysfunction in mice12,24, we did not find any differences in %FS or any other echocardiographic parameters between WT and Scly KO mice on either a high-fructose or a high-dextrose diet. This may be due in part to the sub-strain of our mice compared with these earlier reports. It was recently documented that feeding mice obesogenic diets results in cardiac dysfunction in the C57BL6/J strain only and not the C57BL6/N strain41. Our mice are on the C57BL6/N background, whereas the studies showing cardiac dysfunction after high consumption of fructose are in mice on the C57BL6/J background12,24. The key difference in these WT strains is the nicotinamide (NAD) nucleotide transhydrogenase (Nnt) gene mutation that the C57BL6/J mice harbor42,43 whereas the C57BL6/N mice are WT for this mutation. NNT reduces NADP+ to NADH and is located in the inner membrane of the mitochondria. B6/J mice show higher resting glucose levels and impaired glucose clearance compared to mice without the Nnt mutation44. On a high-fat diet (60% kcal by fat), mean non-fasting glucose levels were higher in B6/J and glucose tolerance was impaired45. The discrepancy between sub-strains emphasizes the need to disclose mouse sub-strains in scientific reports, especially when studying energy homeostasis, and refrain from using the generic “C57BL6” term that abounds in the literature. The discrepancy between prior findings and our study, which did not find any cardiac dysfunction in the WT mice after high-fructose consumption, may hinge on this particular strain detail.

Previous reports in the literature suggest the cardiac lipidome is altered in response to the overconsumption of fructose11,25. We would like to stress that our data analyzing the fatty acid species in the heart does not necessarily contradict these prior studies, as our study includes the added confounder of Se deficiency. Se deficiency alone is associated with altered lipid metabolism46–48. Therefore, this could explain the lack of significant changes in the fatty acid species in our data since our comparisons were between different genotypes, and all were on a Se deficient, high-fructose diet.

The lack of a cardiometabolic phenotype found by a SeMet deficient, high fructose diet also has important implications when considering dietary recommendations for people with a deficiency in Se or for fortifying Se-poor soils. We would like to stress that Se is very important for several biological processes including regulating immune function, reducing oxidative stress, maintaining optimal thyroid function and brain health49,50. Therefore, the form of Se may be very significant when selecting the most effective source for Se supplementation. The maintenance of the antioxidant selenoproteins GPX4 and TXNRD1 in the heart may have also mitigated the cardiometabolic effects produced from the high fructose consumption as Se has been shown to increase the activity of antioxidant proteins including the GPXs in yeast51 and in mammalian cells and tissues52.

In conclusion, we found that loss of Scly combined with a low SeMet, high-fructose diet did not lead to either cardiac or metabolic dysfunction. Such paradigms only reduced GPX1 levels in both male and female Scly KO mice but without impacting cardiovascular function. A compensatory increase in CGL was observed in male Scly KO hearts but not in females, although this does not preclude the existence of a possible Se reservoir in the microbiome in the females. Altogether, we demonstrated that the loss of Scly does not lead to cardiometabolic disorder in mice administered a SeMet deficient, high-fructose diet and suggests that compensatory mechanisms involving Se may be protecting against fructose-induced cardiometabolic disorder.

Limitations of the study

Finally, we would like to address a potential limitation of the study. We chose 8 weeks of diet as previous studies by our laboratory have shown 8 weeks is sufficient to show metabolic disturbances in our Scly KO mouse model30. However, with the better absorption and bioavailability of SeMet compared with selenite32 it is conceivable that even with a longer length of the time, it would still be insufficient to show metabolic impacts of fructose under a low SeMet diet. Despite the elevation in leptin in the Scly KO female mice on a low SeMet, high fructose diet, weight gain was still not observed that could suggest higher food consumption.

Supplementary Material

1

Figure 3. Glucose and insulin tolerance tests in Scly KO mice fed a Se-deficient, high-fructose or high-dextrose diet.

Figure 3.

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After 6 weeks of a 0.08 ppm SeMet, high-fructose diet, a glucose tolerance test was performed. One week later, an insulin tolerance test was performed. A-B. Blood glucose levels in male and female mice during the GTT and AUC quantification. C-D. Blood glucose levels in male and female mice during the ITT and AUC quantification. Each error bar represents mean ± SEM, n values displayed on graphs. AUC was analyzed with a two-tailed t-test with Welch’s correction. AUC graphs were plotted together for visualization purposes. AUC, area under the curve; GTT, glucose tolerance test; ITT, insulin tolerance test.

ACKNOWLEDGEMENTS

This work was supported by grants from the National Institute of General Sciences NIGMS; P20GM139753 to M.J.B, P20GM139753 - Subproject 5203 to B.K.S., the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128390) and an Administrative Supplement (R01DK128390-03S1), and the Ingeborg v. F. McKee Fund of the Hawaii Community Foundation grant #MedRes_2023_00002973 to L.A.S., the Maximizing Access to Research Careers (MARC) program sponsored by the NIGMS grant T34GM141986 to P.J.S., and the National Heart, Lung, and Blood Institute (2T32HL115505-11) to A.G.S. All GC-MS analyses were performed by The University of Hawaii’s Microbial Genomics and Analytical Laboratory Core is supported by NIH NIGMS awards P20GM125508 and P20GM139753.

Footnotes

CONFLICTS OF INTEREST STATEMENT

The authors declare no conflicts of interest.

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