Guo Yuanfang, Wang Jie, Zhang Dongmei, Tang Yufeng, Cheng Quanli, Li Jiahao, Gao Ting, Zhang Xiaohui, Lu Guangping, Liu Mingrui, Guan Xun, Tang Xinyu, Gu Junlian
School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Orthopedic Surgery, the First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China.
Acta Pharm Sin B. 2025 Mar;15(3):1480-1496. doi: 10.1016/j.apsb.2024.12.031. Epub 2025 Jan 2.
Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the promoter and markedly increased expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 () transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific or , along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.
尽管临床证据表明非酒精性脂肪性肝病是心力衰竭的一个既定主要危险因素，但睡眠障碍导致的肝损伤是否会促进心血管疾病（CVD）的发展仍未得到探索。在此，我们的研究结果显示，睡眠片段化（SF）表现出显著的肝脏有害表型，包括脂肪变性和氧化损伤，同时心脏结构和功能也出现明显异常。即使在连续两周或更长时间的睡眠恢复后，所有这些病理变化仍然存在，表现出记忆特性。从机制上讲，肝脏中烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）的持续高表达是SF加速损伤表型的关键启动因素。SF通过表观遗传控制组蛋白H3赖氨酸27（H3K27ac）在启动子处的富集乙酰化，即使在睡眠恢复后，肝脏中的表达也会显著增加。此外，昼夜节律失调后，昼夜节律钟与肝损伤的精细协调受到BMAL1依赖的沉默调节蛋白1（SIRT1）转录的严格控制。因此，对肝脏特异性SIRT1或NOX4进行基因操作，以及针对NOX4（GLX351322）或SIRT1（白藜芦醇）的药物干预，可以通过降低H3K27ac水平有效消除H3K27ac的表观遗传修饰，改善肝脏病理进程，从而对抗SF诱发的持续性CVD。总的来说，我们的研究结果可能为减轻糖尿病患者持续性肝脏有害记忆所致心肌损伤的策略铺平道路。
