Combined Omics Reveals That Disruption of the Selenocysteine Lyase Gene Affects Amino Acid Pathways in Mice

Abstract

Selenium is a nonmetal trace element that is critical for several redox reactions and utilized to produce the amino acid selenocysteine (Sec), which can be incorporated into selenoproteins. Selenocysteine lyase (SCL) is an enzyme which decomposes Sec into selenide and alanine, releasing the selenide to be further utilized to synthesize new selenoproteins. Disruption of the selenocysteine lyase gene (Scly) in mice (Scly−/− or Scly KO) led to obesity with dyslipidemia, hyperinsulinemia, glucose intolerance and lipid accumulation in the hepatocytes. As the liver is a central regulator of glucose and lipid homeostasis, as well as selenium metabolism, we aimed to pinpoint hepatic molecular pathways affected by the Scly gene disruption. Using RNA sequencing and metabolomics, we identified differentially expressed genes and metabolites in the livers of Scly KO mice. Integrated omics revealed that biological pathways related to amino acid metabolism, particularly alanine and glycine metabolism, were affected in the liver by disruption of Scly in mice with selenium adequacy. We further confirmed that hepatic glycine levels are elevated in male, but not in female, Scly KO mice. In conclusion, our results reveal that Scly participates in the modulation of hepatic amino acid metabolic pathways.

Omics insights into the responses to dietary selenium

“…Metabolomics studies in biofluids, tissues, and gut contents after selenium supplementation. Trasnscriptomics and untargeted metabolomics (GC-TOF-MS) [94] Elevated levels of glycine in the liver.…”

“…Untargeted metabolomic analysis after Se supplementation have been performed using mice models [47,73,[85][86][87][88][89][90][91][92][93][94][95][96][97][98], pigs [99][100][101][102], broilers [103], cells [104], rats [105][106][107], gazelle [108], zebra fish [109], humans [110], donkeys [111], salmon [112], and catfish [113]. These studies reported a wide range of altered metabolites after Se supplementation focused on liver [73, 91, 94-96, 100-102, 105, 112] and plasma/serum metabolism [73,92,96,101,105,108,110], but also in muscle [99,103], kidneys [73,93], testes [73], lungs [73,90], spleen [96], blood…”

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

“…The antioxidant selenoprotein, glutathione peroxidase (GPx), functionally links glutathione with selenium, both of which have been implicated as antiviral factors in COVID-19 (414). Selenium exerts its effects largely via the highly-reactive selenocysteine, which is incorporated into selenoproteins, and thereby has close links also to alanine/glycine metabolism (selenocysteine lyase) and the Nrf2 system (thioredoxin reductase-1) (42,63,371). Glutathione is utilised in a range of pathways, and maintaining its cellular concentration depends upon the availability of its precursor amino acids (glutamine, cysteine and glycine).…”

The Possible Mechanism of Physiological Adaptation to the Low-Se Diet and Its Health Risk in the Traditional Endemic Areas of Keshan Diseases

“…However, unlike cysteine (Cys), selenocysteine (Sec) cannot be utilized directly for the aminoacylation of tRNA to produce the Sec-tRNA for the expression of selenoproteins. Sec needs to be broken down by the specific enzyme selenocysteine lyase (Scly) into l -alanine and HSe − (SeMet → Sec → HSe − ) [ 69 – 71 ]. Historically, more attention has been paid to the effect of vitamin B6 on the catalyzation in the Scly step [ 72 – 76 ] rather than the essential role of serine [ 77 ].…”