Selenoproteins Protect Against Avian Liver Necrosis by Metabolizing Peroxides and Regulating Receptor Interacting Serine Threonine Kinase 1/Receptor Interacting Serine Threonine Kinase 3/Mixed Lineage Kinase Domain-Like and Mitogen-Activated Protein Kinase Signaling

Abstract

Liver necroptosis of chicks is induced by selenium (Se)/vitamin E (VE) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms of liver necrosis, a pool of the corn–soy basal diet (10 μg Se/kg; no VE added), a basal diet plus all-rac-α-tocopheryl acetate (50 mg/kg), Se (sodium selenite at 0.3 mg/kg), or both of these nutrients were provided to day-old broiler chicks (n = 40/group) for 6 weeks. High incidences of liver necrosis (30%) of chicks were induced by –SE–VE, starting at day 16. The Se concentration in liver and glutathione peroxidase (GPX) activity were decreased (P < 0.05) by dietary Se deficiency. Meanwhile, Se deficiency elevated malondialdehyde content and decreased superoxide dismutase (SOD) activity in the liver at weeks 2 and 4. Chicks fed with the two Se-deficient diets showed lower (P < 0.05) hepatic mRNA expression of Gpx1, Gpx3, Gpx4, Selenof, Selenoh, Selenok, Selenom, Selenon, Selenoo, Selenop, Selenot, Selenou, Selenow, and Dio1 than those fed with the two Se-supplemented diets. Dietary Se deficiency had elevated (P < 0.05) the expression of SELENOP, but decreased the downregulation (P < 0.05) of GPX1, GPX4, SELENON, and SELENOW in the liver of chicks at two time points. Meanwhile, dietary Se deficiency upregulated (P < 0.05) the abundance of hepatic proteins of p38 mitogen-activated protein kinase, phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, phospho-c-Jun N-terminal kinase, extracellular signal-regulated kinase, phospho-mitogen-activated protein kinase, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like (MLKL) at two time points. In conclusion, our data confirmed the differential regulation of dietary Se deficiency on several key selenoproteins, the RIPK1/RIPK3/MLKL, and mitogen-activated protein kinase signaling pathway in chicks and identified new molecular clues for understanding the etiology of nutritional liver necrosis.

Novel role and mechanism of glutathione peroxidase-4 in nutritional pancreatic atrophy of chicks induced by dietary selenium deficiency

“…In addition, GPX4 mediates the suppression of pyroptosis and ferroptosis in acute pancreatitis [ 22 ]. Although GPX4 is often lowly expressed and is resistant to Se deficiency in mammalian tissues [ 23 ], it is abundantly expressed in chicken tissues and readily affected by Se deficiency [ [24] , [25] , [26] ]. Because of its unique expression pattern in chickens and its potent role in cell death [ [27] , [28] , [29] ], GPX4 might serve as a key selenoprotein involved in the pathogenesis of NPA.…”

Effects of insufficient serine on health and selenoprotein expression in rats and their offspring

“…A possible explanation is that pregnant rats may have an adaptive mechanism to limit maternal serine utilization and ensure adequate supply to the fetus when the supply of serine is insufficient (caused by either insufficient exogenous serine or impaired endogenous serine synthesis) ( 27 , 29 ). This was supported by a decrease in selenoprotein (DIO1/2) synthesis in the maternal organs and tissues but an increase in plasma selenoproteins (SELENOP and GPx3) concentration for transport to the fetus ( 30 ). Furthermore, low expression of liver DIO1/2 did not led to changes in plasma T4 and T3 in pregnant rats either on a low serine diet or given NCT503.…”

Epimedium koreanum Nakai–Induced Liver Injury—A Mechanistic Study Using Untargeted Metabolomics

“…In addition, studies have found that GPX4 is not only an inhibitor of ferroptosis, but also plays an important role in inhibiting necroptosis ( Canli et al, 2016 ). At the same time, some studies have found that the redox homeostasis of cells also plays an important role in necroptosis ( Florean et al, 2019 ; Zhang Y et al, 2020 ; Li et al, 2021 ). Decreased GSH and SOD levels lead to increased oxidative stress in cells, which can induce necroptosis in cells ( Xie et al, 2015 ).…”