The selenium recycling enzyme selenocysteine lyase: regulation and physiological role in glucose and lipid metabolism

Abstract

Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins, acquired either through the diet or cellular recycling mechanisms involving the enzyme selenocysteine lyase (Scly). This dissertation characterizes the Sedependent regulation of Scly gene expression in in vitro and in vivo models. Scly mRNA negatively correlates with Se levels in HepG2 cells, liver and brain tissues, but not in Ht22 cells. Scly is also downregulated in the liver of the Selenoprotein P (Sepp1) knockout (KO) mouse, a model lacking the Se transporter protein with elevated hepatic Se content. Additionally, this dissertation reports the development and characterization of a Scly KO mouse. This mouse model presents diminished Se content and increased expression of selenoprotein mRNAs in the liver compared with wild type mice. Scly KO mice maintain circulating Se levels and most selenoprotein mRNA levels in Se target tissues, such as brain and testis. Disruption of the Scly mechanism also affects hepatic energy metabolism. Scly KO mice raised on a Se adequate diet exhibit hyperinsulinemia and mild hepatic steatosis, with attenuated insulin signaling as measured by Akt phosphorylation and increased oxidative stress, without changes in phosphorylation or protein levels of AMP-activated Protein Kinase alpha, a regulator of cholesterol biosynthesis. On Se restriction, Scly KO mice develop characteristics of metabolic syndrome, such as obesity, fatty liver, hypercholesterolemia and insulin resistance. Moreover, hepatic glutathione peroxidase 1 and circulating Sepp1 levels are also diminished, but mRNA levels of Acetyl-CoA carboxylase are increased. When exposed to a high fat, Se adequate diet, Scly KO mice become more vulnerable to obesity. The findings of this dissertation unveil a strong connection between Se recycling and glucose and lipid metabolism, and demonstrate for the first time in an animal model the unique physiological role of the Se recycling pathway in lipid and glucose metabolism.