Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPK␣). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and selenoprotein S (SelS) production and circulating selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model. S elenium (Se) is an essential trace element acquired through the diet that has been implicated in brain (53), immune, and thyroid function (49), in fertility (2), and in cancer prevention (43). Dietary Se is found in inorganic or organic forms. Se is mostly utilized for biosynthesis of the unique amino acid selenocysteine (Sec), which is cotranslationally incorporated into selenoproteins (36), functioning primarily in redox reactions. The Sec incorporation mechanism involves de novo synthesis of Sec via selenophosphate (SeϳP), which is synthesized by selenophosphate synthetases (SPS) (60). SeϳP is enzymatically attached to the O-phosphoseryl-tRNA, which is then converted to the specific selenocysteyl-tRNA [Ser]Sec used in the selenoprotein translation (54,61). Se is thought to enter the SeϳP pool for Sec biosynthesis either from diet or via recycling after selenoprotein degradation and release of Sec.Selenocysteine lyase (Scly) is responsible for cellular Sec decomposition to mobilize Se for utilization in selenoprotein synthesis (10, 41). Scly was first isolated and characterized from pig liver (18) and subsequently shown to break down Sec into alanine and selenide (41). Scly has been the target of several in vitro studies: it was reported to interact with SPS (58), and its crystal structure revealed the mechanism for the enzyme reaction specificity toward Se (10, 46). In vivo, Scly was recently shown to be involved in selenoprotein biosynthesis in HeLa cells (30). However, the physiological role of Scly in cellular Se metabolism and in vertebrate whole-body Se homeostasis remain...
Background: Selenoproteins play a critical role in neuroprotection. Results: Deletion of selenocysteine lyase (Scly) in combination with selenoprotein P (Sepp1) further aggravates the phenotype of Sepp1 Ϫ/Ϫ mice, as Scly Ϫ/Ϫ Sepp1 Ϫ/Ϫ mice have impaired survival and surviving mice exhibit neurological dysfunction.
Aims: Selenocysteine lyase (Scly) mediates selenocysteine decomposition. It was previously demonstrated that, upon adequate caloric intake (12% kcal fat) and selenium deficiency, disruption of Scly in mice leads to development of metabolic syndrome. In this study, we investigate the effect of a high-fat (45% kcal) seleniumadequate diet in Scly knockout (KO) mice on development of metabolic syndrome. Involvement of selenoproteins in energy metabolism after Scly disruption was also examined in vitro in the murine hepatoma cell line, Hepa1-6, following palmitate treatment. Results: Scly KO mice were more susceptible to diet-induced obesity than their wild-type counterparts after feeding a high-fat selenium-adequate diet. Scly KO mice had aggravated hyperinsulinemia, hypercholesterolemia, glucose, and insulin intolerance, but unchanged inflammatory cytokines and expression of most selenoproteins, except increased serum selenoprotein P (Sepp1). Scly KO mice also exhibited enhanced hepatic levels of pyruvate and enzymes involved in the regulation of pyruvate cycling, such as pyruvate carboxylase (Pcx) and pyruvate dehydrogenase (Pdh). However, in vitro silencing of Scly in Hepa1-6 cells led to diminished Sepp1 expression, and concomitant palmitate treatment decreased Pdh expression. Innovation: The role of selenium in lipid metabolism is recognized, but specific selenium-dependent mechanisms leading to obesity are unclear. This study uncovers that Scly has a remarkable effect on obesity and metabolic syndrome development triggered by high-fat exposure, independent of the expression of most selenoproteins. Conclusion: Diet-induced obesity in Scly KO mice is aggravated, with effects on pyruvate levels and consequent activation of energy metabolism independent of selenoprotein levels. Antioxid. Redox Signal. 23, 761-774.
Chronic delta hepatitis is the most severe form of viral hepatitis affecting nearly 65 million people worldwide. Individuals with this devastating illness are at higher risk for developing cirrhosis and hepatocellular carcinoma. Delta virus is a defective RNA virus that requires hepatitis B surface antigen for propagation in humans. Infection can occur in the form of a co-infection with hepatitis B, which can be self-limiting, vs superinfection in a patient with established hepatitis B infection, which often leads to chronicity in majority of cases. Current noninvasive tools to assess for advanced liver disease have limited utility in delta hepatitis. Guidelines recommend treatment with pegylated interferon, but this is limited to patients with compensated disease and is efficacious in about 30% of those treated. Due to limited treatment options, novel agents are being investigated and include entry, assembly and export inhibitors of viral particles in addition to stimulators of the host immune response. Future clinical trials should take into consideration the interaction of hepatitis B and hepatitis D as suppression of one virus can lead to the activation of the other. Also, surrogate markers of treatment efficacy have been proposed.
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