Endocrinology & Metabolism Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India.
Department of Applied Physiology, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India.
Endocrine. 2018 Jan;59(1):151-163. doi: 10.1007/s12020-017-1463-6. Epub 2017 Nov 11.
High-altitude (HA) environment causes changes in cellular metabolism among unacclimatized humans. Previous studies have revealed that insulin-dependent activation of protein kinase B (Akt) regulates metabolic processes via discrete transcriptional effectors. Moreover, protein arginine methyltransferase (PRMT)1-dependent arginine modification of forkhead box other (FoxO)1 protein interferes with Akt-dependent phosphorylation. The present study was undertaken to test the involvement of PRMT1 on FoxO1 activation during hypobaric hypoxia (HH) exposure in rat model.
Samples were obtained from normoxia control (NC) and HH-exposed (H) rats, subdivided according to the duration of HH exposure. To explore the specific role played by PRMT1 during HH exposure, samples from 1d pair-fed (PF) NC, 1d acute hypoxia-exposed (AH) placebo-treated, and 1d AH TC-E-5003-treated rats were investigated. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) was performed to determine expressions of glycolytic, gluconeogenic enzymes, and insulin response regulating genes. Immuno-blot and enzyme linked immunosorbent assay (ELISA) were used for insulin response regulating proteins. Nuclear translocation of FoxO1 was analyzed using deoxyribonucleic acid (DNA)-binding ELISA kit.
We observed HH-induced increase in glycolytic enzyme expressions in hepatic tissue unlike hypothalamic tissue. PRMT1 expression increased during HH exposure, causing insulin resistance and resulting increase in FoxO1 nuclear translocation, leading to hyperglycemia. Conversely, PRMT1 inhibitor treatment promoted inhibition of FoxO1 activity and increase in glucose uptake during HH exposure leading to reduction in blood-glucose and hepatic glycogen levels.
PRMT1 might have a potential importance as a therapeutic target for the treatment of HH-induced maladies.
高海拔（HA）环境会引起未适应的人体细胞代谢发生变化。先前的研究表明，胰岛素依赖性蛋白激酶 B（Akt）的激活调节代谢过程，通过离散的转录效应物。此外，蛋白精氨酸甲基转移酶（PRMT）1依赖性的 FoxO1 蛋白的精氨酸修饰会干扰 Akt 依赖性磷酸化。本研究旨在检测 PRMT1 在大鼠模型低氧暴露过程中对 FoxO1 激活的参与。
从常氧对照（NC）和低氧暴露（H）大鼠中获得样本，根据低氧暴露的时间进行分组。为了探讨 PRMT1 在低氧暴露期间的特定作用，研究了 1d 配对喂养（PF）NC、1d 急性低氧暴露（AH）安慰剂治疗和 1d AH TC-E-5003 治疗大鼠的样本。采用定量逆转录聚合酶链反应（RT-qPCR）测定糖酵解、糖异生酶和胰岛素反应调节基因的表达。采用免疫印迹和酶联免疫吸附试验（ELISA）检测胰岛素反应调节蛋白。使用脱氧核糖核酸（DNA）结合 ELISA 试剂盒分析 FoxO1 的核转位。
我们观察到低氧诱导肝组织中糖酵解酶表达增加，而下丘脑组织则不同。PRMT1 的表达在低氧暴露期间增加，导致胰岛素抵抗，从而导致 FoxO1 核转位增加，导致高血糖。相反，PRMT1 抑制剂治疗促进了 FoxO1 活性的抑制和低氧暴露期间葡萄糖摄取的增加，导致血糖和肝糖原水平降低。
PRMT1 可能作为治疗低氧诱导疾病的治疗靶点具有重要意义。
