Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates.
Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Human Genetics & Stem Cells Research Group, Research Institute of Sciences & Engineering, University of Sharjah, Sharjah 27272, United Arab Emirates.
Biochim Biophys Acta Gen Subj. 2023 Sep;1867(9):130422. doi: 10.1016/j.bbagen.2023.130422. Epub 2023 Jul 3.
The Hindlimb unloaded mouse, an animal model of simulated microgravity demonstrates significant metabolic and hepatic derangements. However, cellular and molecular mechanisms driving liver dysfunction in Hindlimb unloaded mice are poorly characterized.
We investigated the possible contribution of dysregulated protein homeostasis by endoplasmic reticulum, endoplasmic reticulum stress, to liver dysfunction during HU. C57BL/6j male mice were grouped into ground-based controls or Hindlimb unloaded groups treated daily with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of endoplasmic reticulum stress. Following three weeks of HU, mice were sacrificed, and liver tissues were dissected for further analysis.
Hindlimb unloaded was associated with hepatic atrophy and elevated endoplasmic reticulum stress, which was restored by 4-PBA treatment. The Gene Ontology analysis revealed the downregulation of genes primarily involved in liver metabolic and Wingless-related integration site (WNT) signaling pathways, while those related to cytochrome P450, and liver fibrosis were upregulated. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of several genes involved in metabolic pathways following treatment with 4-PBA, induced by HU.
We report several differential and uniquely expressed genes associated with microgravity-induced elevated ER stress and liver injury. Our data has translational potential in unraveling novel molecular targets for pharmaceutical therapies of liver diseases.
Our novel findings show a pathogenic role for elevated ER stress in liver injury in microgravity conditions.
模拟微重力的后肢去负荷小鼠表现出明显的代谢和肝脏紊乱。然而，导致后肢去负荷小鼠肝脏功能障碍的细胞和分子机制尚未得到充分描述。
我们研究了内质网蛋白稳态失调（内质网应激）在模拟微重力期间对肝脏功能障碍的可能贡献。将 C57BL/6j 雄性小鼠分为地面对照组或后肢去负荷组，每天给予 vehicle 或内质网应激强效抑制剂 4-苯丁酸（4-PBA）处理。后肢去负荷 3 周后，处死小鼠，分离肝脏组织进行进一步分析。
后肢去负荷与肝萎缩和内质网应激升高有关，4-PBA 治疗可恢复内质网应激。GO 分析显示，与肝脏代谢和 Wnt 信号通路相关的基因下调，而与细胞色素 P450 和肝纤维化相关的基因上调。京都基因与基因组百科全书通路分析显示，HU 诱导的内质网应激后，与代谢途径相关的几个基因下调。
我们报告了与 microgravity 诱导的内质网应激升高和肝损伤相关的几个差异表达基因。我们的数据在揭示治疗肝脏疾病的新的药物治疗靶点方面具有转化潜力。
我们的新发现表明，内质网应激升高在微重力条件下的肝脏损伤中起致病作用。
