Seale Lucia A, Gilman Christy L, Hashimoto Ann C, Ogawa-Wong Ashley N, Berry Marla J
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa , Honolulu, Hawaii.
Antioxid Redox Signal. 2015 Oct 1;23(10):761-74. doi: 10.1089/ars.2015.6277. Epub 2015 Aug 24.
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) selenium-adequate 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.
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.
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.
Diet-induced obesity in Scly KO mice is aggravated, with effects on pyruvate levels and consequent activation of energy metabolism independent of selenoprotein levels.
硒代半胱氨酸裂合酶（Scly）介导硒代半胱氨酸的分解。先前的研究表明，在热量摄入充足（脂肪占12%千卡）且缺硒的情况下，敲除小鼠体内的Scly会导致代谢综合征的发生。在本研究中，我们调查了高脂（45%千卡）且硒充足的饮食对Scly基因敲除（KO）小鼠代谢综合征发展的影响。在棕榈酸处理后的小鼠肝癌细胞系Hepa1-6中，还体外检测了Scly缺失后硒蛋白在能量代谢中的作用。
在喂食高脂且硒充足的饮食后，Scly基因敲除小鼠比野生型小鼠更容易发生饮食诱导的肥胖。Scly基因敲除小鼠的高胰岛素血症、高胆固醇血症、血糖和胰岛素耐受性加重，但炎症细胞因子和大多数硒蛋白的表达没有变化，只是血清硒蛋白P（Sepp1）增加。Scly基因敲除小鼠肝脏中的丙酮酸水平以及参与丙酮酸循环调节的酶，如丙酮酸羧化酶（Pcx）和丙酮酸脱氢酶（Pdh）的水平也有所升高。然而，在Hepa1-6细胞中体外沉默Scly会导致Sepp1表达减少，同时棕榈酸处理会降低Pdh表达。
硒在脂质代谢中的作用已得到认可，但导致肥胖的具体硒依赖性机制尚不清楚。本研究发现，Scly对高脂暴露引发的肥胖和代谢综合征发展具有显著影响，且独立于大多数硒蛋白的表达。
Scly基因敲除小鼠的饮食诱导肥胖加剧，对丙酮酸水平有影响，并因此激活能量代谢，且与硒蛋白水平无关。
