高原低氧胁迫对小鼠肝脏功能及基因表达的影响
收稿日期: 2022-06-01
录用日期: 2022-08-17
网络出版日期: 2022-09-21
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
Received date: 2022-06-01
Accepted date: 2022-08-17
Online published: 2022-09-21
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。
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 . DOI: 10.16829/j.slxb.150697
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
| null | Bogdanova A, Petrushanko I Y, Hernansanz?Agustín P, Martínez?Ruiz A. 2016.‘Oxygen sensing’by Na, K-ATPase: these miraculous thiols. Frontiers in Physiology, 7: 314. |
| null | Cargnello M, Roux P P. 2011. Activation and function of the mapks and their substrates, the mapk?activated protein kinases. Microbiology and Molecular Biology Reviews, 75 (1): 50-83. |
| null | Chen H J, Edwards R, Tucci S, Bu P, Milsom J, Lee S, Edelmann W, Gümüs Z H, Shen X, Lipkin S. 2012. Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis. The Journal of Clinical Investigation, 122 (9): 3184-3196. |
| null | Chen M X, Shen H, Zhu L L, Yang H F, Ye P, Liu P F, Gu Y, Chen S L. 2019. Berberine attenuates hypoxia-induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor-β signaling. Journal of Cellular Physiology, 234 (10): 17482-17493. |
| null | Corless J K, Middleton H M. 1983. Normal liver function. A basis for understanding hepatic disease. Archives of Internal Medicine, 143 (12): 2291-2294. |
| null | Cursio R, Miele C, Filippa N, Van Obberghen E, Gugenheim J. 2008. Liver HIF?1 alpha induction precedes apoptosis following normothermic ischemia-reperfusion in rats. Transplantation Proceedings, 40 (6): 2042-2045. |
| null | Henne M. 2019. And three’s a party: lysosomes, lipid droplets, and the ER in lipid trafficking and cell homeostasis. Current Opinion in Cell Biology, 59: 40-49. |
| null | Hou Y P, Yang H A, Cui Z S, Tai X H, Chu Y L, Guo X. 2017. Tauroursodeoxycholic acid attenuates endoplasmic reticulum stress and protects the liver from chronic intermittent hypoxia induced injury. Experimental and Therapeutic Medicine, 14 (3): 2461-2468. |
| null | Huang Y, Li X H, Wang Y R, Wang H, Huang C, Li J. 2014. Endoplasmic reticulum stress?induced hepatic stellate cell apoptosis through calcium?mediated JNK/P38 MAPK and Calpain/Caspase-12 pathways. Molecular and Cellular Biochemistry, 394 (1-2): 1-12. |
| null | Huang Y, Wang D D, Wang X, Zhang Y J, Liu T, Chen Y T, Tang Y H, Wang T, Hu D, Huang C X. 2016. Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction. Scientific Reports, 6: 32660. |
| null | Hernández?Bustabad A, Morales?Arraez D, González?Paredes F J, Abrante B, Diaz?Flores F, Abreu?Gonzalez P, de la Barreda R, Quintero E, Hernández?Guerra M. 2022. Chronic intermittent hypoxia promotes early intrahepatic endothelial impairment in rats with non?alcoholic fatty liver disease. American Journal of Physiology. Gastrointestinal and Liver Physiology.DOI: 10.1152/ajpgi.00300.2021 . |
| null | Jin S, Chen Z, Lunan Y, Zeng Y, Wen T, Li B, Zhao J, Wang W, Xu M, Yang J. 2009. Can liver transplantation achieve similar effects at high altitudes compared with plains: case report. Transplantion Proceedings, 41 (5): 2003-2005. |
| null | Ke Q, Costa M. 2006. Hypoxia-inducible factor-1 (HIF?1). Molecular Pharmacology, 70 (5): 1469-1480. |
| null | Kang H H, Kim I K, Lee H I, Joo H, Lim J U, Lee J, Lee S H, Moon H S. 2017. Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways. Biochemical and Biophysical Research Communications, 490 (2): 349-355. |
| null | Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly?Maitre B. 2018. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. Journal of Hepatology, 69 (4): 927-947. |
| null | Li W B, Jia Z P, Xie H, Zhang J H, WangY L, Hao Y, Wang R.2014. Effects of acute exposure to high altitude on hepatic function and CYP 1A2 and CYP 3A4 activities in rats. Journal of Southern Medical University, 34: 1203-1206. |
| null | Liu F Y, Hu L, Li Y X, Liu S M, Tang Y P, Qi S G, Yang L, Wu T Y. 2015. Effect of altitude chronic hypoxia on liver enzymes and its correlation with ACE/ACE2 in yak and migrated cattle. Chinese Journal of Applied Physiology, 31 (3): 272. |
| null | Lukas J, Pospech J, Oppermann C, et al. 2019. Role of endoplasmic reticulum stress and protein misfolding in disorders of the liver and pancreas. Advances in Medical Sciences, 64 (2): 315-323. |
| null | Li S, Yang Q E. 2022. Hypobaric hypoxia exposure alters transcriptome in mouse testis and impairs spermatogenesis in offspring. Gene, 823: 146390. |
| null | Madrigal?Santillán E, Madrigal?Bujaidar E, álvarez?González I, Sumaya?Martínez M T, Gutiérrez?Salinas J, Bautista M, Morales?González á, García?Luna Y, González?Rubio M, Aguilar?Faisal J L, Morales?González J A. 2014. Review of natural products with hepatoprotective effects. World Journal of Gastroenterology, 20 (40): 14787-14804. |
| null | Mylonis I, Chachami G, Paraskeva E, Simos G. 2008. Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1alpha by MAPK. The Journal of Biological Chemistry, 283 (41): 27620-27627. |
| null | Nath B, Szabo G. 2012. Hypoxia and hypoxia inducible factors: diverse roles in liver diseases. Hepatology, 55 (2): 622-633. |
| null | Piret J P, Mottet D, Raes M, Michiels C. 2002. CoCl2, a chemical inducer of hypoxia-inducible factor-1, and hypoxia reduce apoptotic cell death in hepatoma cell line HepG2. Annals of the New York Academy of Sciences, 973 (1): 443-447. |
| null | Patel J C, Khurana P, Sharma Y K, Kumar B, Ragumani S. 2018. Chronic lifestyle diseases display seasonal sensitive comorbid trend in human population evidence from Google Trends. PLoS ONE, 13 (12): e0207359. |
| null | Reed W A, Manning R T, Hopkins L T.1964. Effects of hypoxia and hyperthermia on hepatic tissue of the dog. American Journal of Physiology, 206 (6): 1304. |
| null | Rius B, Duran?Güell M, Flores?Costa R, López?Vicario C, Lopategi A, Alcaraz?Quiles J, Casulleras M, Lozano J J, Titos E, Clària J. 2017. The specialized proresolving lipid mediator maresin 1 protects hepatocytes from lipotoxic and hypoxia-induced endoplasmic reticulum stress. The Federation of American Societies for Experimental Biology, 31 (12): 5384-5398. |
| null | Shingu K, Eger E I, Johnson B H. 1982. Hypoxia per se can produce hepatic damage without death in rats. Anesthesia and Analgesia, 61 (10): 820-823. |
| null | Song M J, Malhi H. 2019.The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacology & Therapeutics, 203: 107401. |
| null | Tian Y M, Liu Y, Wang S, Dong Y, Su T, Ma H J, Zhang Y. 2016. Anti-diabetes effect of chronic intermittent hypobaric hypoxia through improving liver insulin resistance in diabetic rats. Life Sciences, 150: 1-7. |
| null | Troeger J S, Schwabe R F. 2011. Hypoxia and hypoxia-inducible factor 1α: potential links between angiogenesis and fibrogenesis in hepatic stellate cells. Liver International: Official Journal of the International Association for the Study of the Liver, 31 (2): 143-145. |
| null | Tao H P, Jia G X, Zhang X N, Wang Y J, Li B Y, Yang Q E. 2022. Paternal hypoxia exposure impairs fertilization process and preimplantation embryo development. Zygote, 30 (1): 48-56. |
| null | Vicari A P, Figueroa D J, Hedrick J A, Foster J S, Singh K P, Menon S, Copeland N G, Gilbert D J, Jenkins N A, Bacon K B, Zlotnik A. 1997. TECK: a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development. Immunity, 7 (2): 291-301. |
| null | Wang Y Q, Huang Y M, Guan F, Xiao Y, Deng J, Chen H Y, Chen X L, Li J R, Huang H J, Shi C W. 2013. Hypoxia-inducible factor-1alpha and MAPK co?regulate activation of hepatic stellate cells upon hypoxia stimulation. PLoS ONE, 8 (9): e74051. |
| null | Watt M J, Miotto P M, De Nardo W, Montgomery M K. 2019. The liver as an endocrine organ?linking NAFLD and insulin resistance. Endocrine Reviews, 40 (5): 1367-1393. |
| null | Xiong Y L, Wang Y M, Xiong Y L, Gao W, Teng L H. 2020. Salidroside alleviated hypoxia-induced liver injury by inhibiting endoplasmic reticulum stress?mediated apoptosis via IRE1α/JNK pathway. Biochemical and Biophysical Research Communications, 529 (2): 335-340. |
| null | Yuen V W, Wong C C. 2020. Hypoxia-inducible factors and innate immunity in liver cancer. The Journal of Clinical Investigation, 130 (10): 5052-5062. |
| null | Zaballos A, Gutiérrez J, Varona R, Ardavín C, Márquez G. 1999. Cutting edge: identification of the orphan chemokine receptor GPR- 9-6 asCCR9, the receptor for the chemokine TECK. Journal of immunology (Baltimore, Md.: 1950), 162 (10): 5671-5675. |
| null | 冯恩志, 戴胜归, 杨生岳. 2014. 低氧性肺动脉高压研究进展. 中华肺部疾病杂志, 7 (3): 84-87. |
| null | 杜继曾, 张家兴. 2004. 低氧下生长发育抑制与认知功能促进的调节机制.珠海: 中国生理学会第五届比较生理学学术会议, 16-17. |
| null | 杜继曾, 李庆芬. 1982. 模拟高原低氧对高原鼠兔和大鼠器官与血液若干指标的影响. 兽类学报, 2 (1): 35-42. |
| null | 李永慧, 李永芳, 杨梅. 2016. 唐古特青兰对高原低氧大鼠肝损伤的保护作用. 高原医学杂志, 26 (2): 6-9. |
| null | 荣黎, 曾维政, 吴晓玲. 2009. 高原缺氧与肝脏损伤. 世界华人消化杂志, 8: 189-195. |
| null | 程守科, 于军一, 司本辉, 肖庆林, 梁子钧. 2001. 高原低氧环境下红细胞增多和血液粘度间关系的研究. 中国应用生理学杂志, 17 (3): 231-235. |
| null | 廖卫公, 高钰琪, 吴艺, 蔡明春, 范有明. 2006. 低氧对大鼠附睾功能的影响. 生殖医学杂志, 15 (4): 252-256. |
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