高原低氧胁迫对小鼠肝脏功能及基因表达的影响

doi:10.16829/j.slxb.150697

兽类学报 ›› 2022, Vol. 42 ›› Issue (5): 590-600.DOI: 10.16829/j.slxb.150697

高原低氧胁迫对小鼠肝脏功能及基因表达的影响

陶海萍¹^,², 李双¹^,², 贾功雪¹^,⁴, 张璐瑶³, 方有贵⁵, 陈永伟⁶, 杨其恩¹^,⁴()

^1.中国科学院西北高原生物研究所，中国科学院高原生物适应与进化重点实验室，西宁 810001
^2.中国科学院大学，北京 100049
^3.中国农业大学农业生物学院生物技术国家重点实验室，北京 100193
^4.中国科学院西北高原生物研究所，青海省动物基因组学重点实验室，西宁 810001
^5.玛多县农牧综合服务中心，果洛 813599
^6.青海省畜牧总站，西宁 810008

收稿日期:2022-06-01 接受日期:2022-08-17 出版日期:2022-09-30 发布日期:2022-09-21
通讯作者: 杨其恩
作者简介:陶海萍 (1995- )，女，硕士研究生，主要从事哺乳动物发育生物学研究.
基金资助:
青海省重大专项“三江源区代表性动物基因资源保护与利用”;中国科学院青年创新促进会(2021432);青海省“昆仑英才”·高端创新创业人才

Effects of hypoxia stress on liver function and gene expression in mice

Haiping TAO¹^,², Shuang LI¹^,², Gongxue JIA¹^,⁴, Luyao ZHANG³, Yougui FANG⁵, Yongwei CHEN⁶, Qien YANG¹^,⁴()

^1.Key Laboratory of Adaptation and Evolution of Plateau Biota, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001, China
^2.University of Chinese Academy of Sciences, Beijing 100049, China
^3.State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
^4.Qinghai Provincial Key Laboratory of Animal Ecological Genomics, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810001, China
^5.Maduo Agriculture and Animal Husbandry Service Center, Guoluo 813599, China
^6.Qinghai Animal Husbandry Station, Xining 810008, China

Received:2022-06-01 Accepted:2022-08-17 Online:2022-09-30 Published:2022-09-21
Contact: Qien YANG

摘要/Abstract

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

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

中图分类号:

Q494

陶海萍, 李双, 贾功雪, 张璐瑶, 方有贵, 陈永伟, 杨其恩. 高原低氧胁迫对小鼠肝脏功能及基因表达的影响[J]. 兽类学报, 2022, 42(5): 590-600.

Haiping TAO, Shuang LI, Gongxue JIA, Luyao ZHANG, Yougui FANG, Yongwei CHEN, Qien YANG. Effects of hypoxia stress on liver function and gene expression in mice[J]. ACTA THERIOLOGICA SINICA, 2022, 42(5): 590-600.

图/表 7

图1 高原低氧环境对小鼠体重及器官比重的影响. 右心指数 (A)、18周体重 (B)、肺脏比重 (C) 和肝脏比重 (D). n = 9. *P < 0.05，**P < 0.01

Fig.1 Effects of plateau hypoxic environment on body weight and organ proportion of mice. Right heart index (A), body weight at 18 weeks (B), lung specific gravity (C) and liver specific gravity (D). n = 9. *P < 0.05, **P < 0.01

图2 高原低氧环境对小鼠肝脏组织形态的影响.常氧和低氧第0 ~ 5代肝脏HE染色代表性图. 标尺 = 15 μm.红细胞浸润 (黄色箭头)，肝小叶内脂滴空泡 (绿色三角)

Fig.2 Effects of plateau hypoxic environment on liver tissue morphology of mice. Representative images of HE staining of normoxic and hypoxic livers from generation 0 to generation 5. Scale bars represent 15 μm.Red blood cell infiltration (yellow arrow), intralobular lipid vacuoles (green triangle)

图3 高原低氧环境对小鼠血液生化指标的影响.谷丙转氨酶 (A)，谷草转氨酶 (B)，白蛋白 (C)，球蛋白 (D)，总胆红素 (E)，总胆固醇 (F). n = 3.不同字母代表各组间有显著性差异 (P < 0.05)

Fig.3 Effects of plateau hypoxic environment on biochemical indexes of mice. Alanine aminotransferase (ALT) (A), aspartate aminotransferase (AST) (B), albumin (C), globulin (D), total bilirubin (E), total cholesterol (F). n = 3. Bars with different letters were significantly different (P < 0.05)

图4 高原低氧环境对小鼠血糖水平和胰岛素水平的影响. GTT血糖浓度 (A)，GTT血清胰岛素水平 (B)和ITT血糖浓度 (C). n = 3.不同字母代表各组间有显著性差异 (P < 0.05)

Fig.4 Effects of plateau hypoxic environment on blood sugar and insulin levels of mice. GTT blood glucose concentration (A), GTT serum insulin level (B), ITT blood glucose concentration (C). n = 3.Bars with different letters were significantly different (P < 0.05)

图5 低氧和常氧小鼠肝脏差异表达基因分析.低氧第0代 vs. 常氧第0代，低氧第1代 vs. 常氧第0代和低氧第1代 vs. 低氧第0代差异表达基因数量 (A ~ C) 和热图 (D ~ E)

Fig.5 The differentially expressed gene analysis of mice liver in Hypoxic group and Normoxic group. Numbers of differentially expressed gene (A ? C) and Heatmap (D ? E) of Hypoxic generation 0 vs. Normoxic generation 0, Hypoxic generation 1 vs. Normoxic generation 0 and Hypoxic generation 1 vs. Hypoxic generation 0

图6 低氧与常氧小鼠肝脏差异表达基因分析.低氧第0代 vs.常氧第0代，低氧第1代 vs.常氧第0代和低氧第1代 vs.低氧第0代差异基因数量维恩图 (A) 和KEGG通路分析图 (B ~ D)

Fig.6 The differentially expressed gene analysis of mice liver in Hypoxic group and Normoxic group. The Venn diagram of differentially expressed gene (A) and KEGG pathway analysis diagram (B ? D) of Hypoxic generation 0 vs.Normoxic generation 0, Hypoxic generation 1 vs.Normoxic generation 0 and Hypoxic generation 1 vs.Hypoxic generation 0

图7 低氧小鼠肝脏差异基因表达分析.低氧第0代与低氧第1代差异表达基因的GO分析 (A，B)，MAPK信号通路相关基因的mRNA FPKM表达量 (C). 不同字母代表各组间有显著性差异 (P < 0.05)

Fig. 7 Effects of exposure to high altitude hypoxia on next generation liver. GO analysis of differentially expressed gene between Hypoxic generation 0 and Hypoxic generation 1 (A, B), mRNA FPKM expression level of genes related to MAPK signaling pathway (C). Bars with different letters were significantly different (P < 0.05)

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高原低氧胁迫对小鼠肝脏功能及基因表达的影响

Effects of hypoxia stress on liver function and gene expression in mice

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