Abstract:

As one of the most characteristic environmental factors on the Qinghai-Tibet Plateau, hypoxia has a profound impact on the adaptive evolution of plateau animals. Continued exposure to a hypoxic environment causes metabolic dysfunction of the body. In non-acclimated animals, long-term hypoxia exposure affects liver function, but there is still a lack of knowledge regarding its effect on offspring liver. In this study, adult mice were transferred to a high altitude hypoxic environment (altitude 3 220 m) for breeding. Mice reared under normoxic conditions were used as a control and the growth and live function of hypoxic-treated mice (hypoxic generation 0) and their offspring (hypoxic generation 1 ? generation 5) were evaluated.The results showed that long-term hypoxia exposure led to morphological and functional changes in the liver. Hepatocytes of hypoxia-exposed animals were swollen, caused by red blood cells infiltrating between hepatic cords. Specifically, the fatty degeneration appeared in the liver lobules of hypoxic generation 1 mice. Blood biochemical analyses showed that compared with the normoxia generation 0, the levels of alanine aminotransferase and aspartate aminotransferase in hypoxia generation 0 and hypoxia generation 1 increased significantly (P < 0.05).Albumin, globulin, total bilirubin and total cholesterol levels decreased in hypoxia generation 0 and increase in hypoxia generation 1 (P < 0.05). After fasting injection of glucose and insulin, the glucose tolerance and insulin sensitivity of mice in the hypoxic group were greatly reduced (P < 0.05). RNA-seq analysis of liver tissue from normoxic generation 0, hypoxic generation 0, and hypoxic generation 1 identified 459 differential expression genes (DEGs) in livers of hypoxia-exposed animals. These genes were significantly enriched in the MAPK signaling pathway, apoptosis, lipid metabolism, and endoplasmic reticulum pathway. This study demonstrated that hypoxic exposure has important effects on the liver in mice and the outcomes of these findings provide information to further elucidate the physiological and pathological changes induced by hypoxia at high altitudes.

Key words: Altitude hypoxia, Mice, Liver function, Liver transcriptome, Metabolize

摘要：

低氧作为青藏高原最为特殊的环境因素之一，对高原动物的适应进化产生了深刻的影响。持续的低氧暴露会损伤肝脏功能，引起动物机体代谢紊乱，但连续低氧处理对子代肝脏的影响仍缺乏相关研究。本研究将成年小鼠转移至高原低氧环境 (海拔3 220 m) 饲养并繁殖，以常氧条件下饲养小鼠为对照，统计低氧处理小鼠 (低氧第0代) 及其子代 (低氧第1 ~ 5代) 生长数据，发现长期低氧暴露导致小鼠肝脏比重增加，肝细胞肿胀，肝索间红细胞浸润，并且子一代小鼠肝小叶出现脂肪变性。血液生化指标显示，相比于对照组 (常氧第0代)，低氧第0代和低氧第1代的谷丙转氨酶和谷草转氨酶水平显著上升 (P < 0.05)；血清白蛋白、球蛋白、总胆红素和总胆固醇水平在低氧第0代中下降，低氧第1代中上升 (P < 0.05)。空腹注射葡萄糖和胰岛素后低氧组小鼠的葡萄糖耐受能力和胰岛素敏感性显著减弱 (P < 0.05)。常氧第0代、低氧第0代及低氧第1代肝脏RNA-seq分析发现，低氧第0代和低氧第1代共有的459个差异基因显著富集在MAPK、细胞凋亡、脂质代谢和内质网等信号通路。本研究发现低氧胁迫对子代小鼠肝脏具有重要影响，此结果对肝脏低氧生理和高原肝脏疾病的研究具有重要的借鉴意义。

关键词: 高原低氧, 小鼠, 肝脏功能, 肝脏转录组, 代谢