Waseda Institute for Advanced Study, Waseda University, Shinjuku-ku, Tokyo, 162-8480, Japan.
Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Wakamatsu-cho 2-2, Shinjuku-ku, Tokyo, 162-8480, Japan.
Nat Rev Gastroenterol Hepatol. 2016 Apr;13(4):217-26. doi: 10.1038/nrgastro.2016.8. Epub 2016 Feb 24.
The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.
生物钟系统由位于下丘脑视交叉上核的中央时钟和外周组织中的外周时钟组成。肝脏中的外周时钟在维持肝脏内稳态方面发挥着重要作用，包括调节能量代谢和控制吸收和代谢外来物质的酶的表达。在过去的二十年中，研究人员使用全局时钟基因敲除小鼠，或具有肝脏特异性时钟基因或时钟控制基因敲除的小鼠，研究了将生物钟基因与肝脏生理功能调节联系起来的分子机制。时钟功能障碍会加速脂肪肝、肝硬化、肝炎和肝癌等肝脏疾病的发展，而这些疾病也会破坏时钟功能。食物是外周组织生物钟的重要调节剂。因此，控制食物摄入的时间和食物成分，即所谓的时间营养，是帮助恢复许多生理功能障碍的一个活跃研究领域。在这篇综述中，我们重点介绍了肝脏生物钟基因调节的分子机制，以及肝脏生物钟系统与肝脏生理学和疾病之间的关系。我们集中讨论了从细胞或小鼠和大鼠模型中获得的实验数据，并讨论了这些发现如何转化为临床研究，还强调了时间营养研究的最新进展。
