Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, 33155, USA.
Institute for Diabetes and Cancer (IDC), Helmholtz Diabetes Center, Helmholtz Centre Munich, Neuherberg, Germany.
Mol Cell Biochem. 2023 Mar;478(3):581-595. doi: 10.1007/s11010-022-04536-8. Epub 2022 Aug 17.
We evaluated the mechanistic link between circadian rhythms and gut barrier permeability. Mice were subjected to either constant 24-h light (LL) or 12-h light/dark cycles (LD). Mice housed in LL experienced a significant increase in gut barrier permeability that was associated with dysregulated ß-catenin expression and altered expression of tight junction (TJ) proteins. Silencing of ß-catenin resulted in disruption of barrier function in SW480 cells, with ß-catenin appearing to be an upstream regulator of the core circadian components, such as Bmal1, Clock, and Per1/2. In addition, ß-catenin silencing downregulated ZO-1 and occludin TJ proteins with only limited or no changes at their mRNA levels, suggesting post transcriptional regulation. Indeed, silencing of ß-catenin significantly upregulated expression of matrix metallopeptidase (MMP)-2 and MMP-9, and blocking MMP-2/9 activity attenuated epithelial disruption induced by ß-catenin silencing. These results indicate the regulatory role of circadian disruption on gut barrier integrity and the associations between TJ proteins and circadian rhythms, while demonstrating the regulatory role of ß-catenin in this process.
我们评估了昼夜节律与肠道屏障通透性之间的机制联系。将小鼠置于持续 24 小时光照（LL）或 12 小时光照/黑暗循环（LD）中。在 LL 环境中饲养的小鼠肠道屏障通透性显著增加，这与 β-连环蛋白表达失调和紧密连接（TJ）蛋白表达改变有关。β-连环蛋白沉默导致 SW480 细胞的屏障功能破坏，β-连环蛋白似乎是核心生物钟成分（如 Bmal1、Clock 和 Per1/2）的上游调节剂。此外，β-连环蛋白沉默下调 ZO-1 和 occludin TJ 蛋白，其 mRNA 水平仅有限或无变化，提示转录后调控。事实上，β-连环蛋白沉默显著上调基质金属蛋白酶（MMP）-2 和 MMP-9 的表达，阻断 MMP-2/9 活性可减弱 β-连环蛋白沉默诱导的上皮破坏。这些结果表明昼夜节律紊乱对肠道屏障完整性的调节作用以及 TJ 蛋白与昼夜节律之间的关联，同时证明了 β-连环蛋白在这一过程中的调节作用。
