昼夜节律与肝损伤

doi:10.6040/j.issn.1671-7554.0.2026.0952

摘要/Abstract

摘要： 昼夜节律是机体适应光暗交替、摄食周期和环境变化形成的内源性时间调控机制,其核心由昼夜节律调控蛋白(clock circadian regulator, CLOCK)、碱性螺旋-环-螺旋ARNT样蛋白1(basic helix-loop-helix ARNT like 1,BMAL1)、周期基因(period, PER)、隐花色素基因(cryptochrome, CRY)、REV-ERB核受体(REV-ERB nuclear receptor, REV-ERB)和视黄酸受体相关孤儿受体(retinoic acid receptor-related orphan receptor, ROR)等时钟分子构成的转录-翻译反馈环维持。肝脏是机体最重要的代谢、解毒和免疫调节器官,也是典型的外周节律器官。肝脏糖脂代谢、胆汁酸合成、药物代谢、线粒体氧化磷酸化、抗氧化防御和免疫炎症反应均具有明显节律性。近年研究发现,昼夜节律紊乱不仅参与代谢相关脂肪性肝病、药物性肝损伤、酒精性肝病、胆汁淤积性肝损伤、肝缺血再灌注损伤和肝纤维化等多种肝损伤性肝病,而且通过调控胰岛素抵抗、氧化应激、炎症反应、自噬、内质网应激和多种形式的调节性细胞死亡等机制影响肝脏损伤。反之,肝损伤状态下的脂质蓄积、缺氧、炎症因子释放和代谢重编程也可破坏肝脏局部生物钟,形成“节律紊乱-代谢失衡-损伤加重”的恶性循环。本文综述昼夜节律的分子基础及其在肝脏代谢稳态中的作用,重点阐述昼夜节律参与不同类型肝损伤的机制联系,并探讨时间限制进食、时间药理学和靶向时钟网络及其下游效应通路的潜在治疗价值,以期为肝损伤防治提供新的理论依据和转化方向。

关键词: 昼夜节律, 肝损伤, 肝脏代谢, 胰岛素抵抗, 炎症反应, 细胞死亡, 时间药理学

Abstract: Circadian rhythm is an endogenous timekeeping system that enables organisms to adapt to light-dark cycles, feeding rhythms and environmental changes. At the molecular level, circadian oscillation is maintained by transcriptional-translational feedback loops composed of clock circadian regulator(CLOCK), basic helix-loop-helix ARNT like 1(BMAL1), period(PER), cryptochrome(CRY), REV-ERB nuclear receptor(REV-ERB)and retinoic acid receptor-related orphan receptor(ROR). The liver is a central organ for metabolism, detoxification and immune regulation, and also a typical peripheral clock organ. Hepatic glucose and lipid metabolism, bile acid synthesis, xenobiotic metabolism, mitochondrial oxidative phosphorylation, antioxidant defense and immune responses exhibit robust circadian oscillations. Accumulating evidence indicates that circadian disruption contributes to a variety of liver injury-related disorders, including metabolic dysfunction-associated steatotic liver disease, drug-induced liver injury, alcoholic liver disease, cholestatic liver injury, hepatic ischemia/reperfusion injury and liver fibrosis. Mechanistically, circadian clocks regulate liver injury by modulating insulin resistance, oxidative stress, inflammatory responses, autophagy, endoplasmic reticulum stress and multiple forms of regulated cell death. Conversely, hepatic injury-associated lipid accumulation, hypoxia, inflammatory cytokine release and metabolic reprogramming may disturb local hepatic clocks, forming a vicious cycle of circadian disruption, metabolic imbalance and aggravated liver injury. This review summarized the molecular basis of circadian rhythm and its role in hepatic metabolic homeostasis, highlighted the mechanistic links between circadian clocks and liver injury, and discussed potential therapeutic strategies based on chronobiology.

Key words: Circadian rhythm, Liver injury, Hepatic metabolism, Insulin resistance, Inflammation, Cell death, Chronopharmacology

中图分类号:

R575

瞿泽同,马春红. 昼夜节律与肝损伤[J]. 山东大学学报 (医学版), 2026, 64(10): 1-15.

QU Zetong, MA Chunhong. Circadian rhythm and liver injury[J]. Journal of Shandong University (Health Sciences), 2026, 64(10): 1-15.

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