Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 756-0884, Yamaguchi, Japan.
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi, Japan.
Mol Biol Rep. 2022 Dec;49(12):11881-11890. doi: 10.1007/s11033-022-07940-x. Epub 2022 Oct 12.
Diabetes patients are at a high risk of developing complications related to angiopathy and disruption of the signal transduction system. The liver is one of the multiple organs damaged during diabetes. Few studies have evaluated the morphological effects of adhesion factors in diabetic liver. The influence of diurnal variation has been observed in the expression and functioning of adhesion molecules to maintain tissue homeostasis associated with nutrient uptake. The present study demonstrated that the rhythm-influenced functioning of tight junction was impaired in the liver of ob/ob mice. The tight junctions of hepatocytes were loosened during the dark period in control mice compared to those in ob/ob mice, where the hepatocyte gaps remained open throughout the day. The time-dependent expression of zonula occludens 1 (ZO1, encoded by Tjp1 gene) in the liver plays a vital role in the functioning of the tight junction. The time-dependent expression of ZO1 was nullified and its expression was attenuated in the liver of ob/ob mice. ZO1 expression was inhibited at the mRNA and protein levels. The expression rhythm of ZO1 was found to be regulated by heat shock factor (HSF)1/2, the expression of which was reduced in the liver of ob/ob mice. The DNA-binding ability of HSF1/2 was decreased in the liver of ob/ob mice compared to that in control mice. These findings suggest the involvement of impaired expression and functioning of adhesion factors in diabetic liver complications.
糖尿病患者发生与血管病变和信号转导系统紊乱相关并发症的风险较高。肝脏是糖尿病患者多个受损器官之一。目前，很少有研究评估黏附因子对糖尿病肝脏的形态影响。已有研究表明，昼夜变化会影响黏附分子的表达和功能，从而维持与营养摄取相关的组织内稳态。本研究表明，ob/ob 小鼠肝脏中紧密连接的节律性功能受到影响。与 ob/ob 小鼠相比，在对照小鼠中，肝细胞的紧密连接在黑暗期会松弛，而 ob/ob 小鼠的肝细胞间隙全天保持开放。肝脏中闭锁小带蛋白 1（zonula occludens 1，Tjp1 基因编码）的时间依赖性表达对紧密连接的功能至关重要。ob/ob 小鼠肝脏中 ZO1 的时间依赖性表达被消除，其表达减弱。ZO1 的表达在 mRNA 和蛋白质水平上受到抑制。研究发现，ZO1 的表达节律受热休克因子（heat shock factor，HSF）1/2 调控，ob/ob 小鼠肝脏中 HSF1/2 的表达减少。与对照小鼠相比，ob/ob 小鼠肝脏中 HSF1/2 的 DNA 结合能力降低。这些发现提示，黏附因子表达和功能受损可能参与了糖尿病肝脏并发症的发生。
