Circadian regulation of liver energy metabolism: translational studies in diabetes and obesity

肥胖是一个非常常见的健康问题，对肝功能有重大影响。当脂肪在肝脏中积聚时，可能会导致功能异常，包括胰岛素抵抗和II型糖尿病。此外，肝脏炎症促使肝脏从非酒精性脂肪性肝病(NAFLD)到非酒精性脂肪性肝炎(NASH--一种肝炎)，再到肝硬变和肝癌。每个人体内都有生物钟，或称“昼夜节律”，这种生物钟内置在每个细胞中，帮助身体运转。有新的证据表明，肝脏中有一个控制脂肪代谢的生物钟。这为如何阻断上述疾病的发展提供了一个新的视角。在这里，我将检验这样一个假设，即肝脏中的生物钟和昼夜代谢回路可以受到营养供应的影响，我还将进一步测试与摄食和能量代谢有关的信号媒介(化学物质)的作用，包括神经酰胺(源自肠道上皮的鞘磷脂)和短链脂肪酸(肠道微生物群的产物，具有肝脏调节活性)。我将使用原代人类肝细胞为这些研究创造肝脏“类器官”(微肝脏)。同时，我将使用原代小鼠肝细胞，因为这些细胞也提供了使用携带生物钟报告基因的转基因小鼠的细胞的机会，我可以通过多个生物钟周期实时跟踪这些基因，此外，我还可以选择性地删除特定的生物钟成分，包括基因BMAL1和REVERBA。我将继续使用这个有机系统来研究以肝脏中的生物钟为靶点如何调节营养感知和对涉及能量转换的代谢物的处理。通过这种方式，我可以使用小的类药物分子来调节时钟(例如，隐色素激活剂和混响配体)，同时选择性地删除BMAL1(停止生物钟)或REVERBA(中断生物钟和肝脏脂肪生产计划之间的连接)等基因。我将确定来自摄食的信号，包括葡萄糖、脂肪酸，以及包括短链脂肪酸和神经酰胺在内的信号媒介，如何影响核心肝脏时钟，并影响生物钟控制的代谢网络。我将继续发现时钟的运行如何影响代谢变化的处理，在代谢变化中，葡萄糖和脂肪酸受到氧化，或者在葡萄糖发生脂肪生成的情况下。我将有机会进一步测试这个系统在应对炎症信号时的完整性，比如患有类风湿性关节炎等慢性炎症性疾病的人所经历的那些信号，或者是肥胖的一个一贯特征--慢性低度炎症。

Obesity is a very common health issue, with a major impact on liver function. When fat builds up in the liver, this can lead to abnormal function, including insulin resistance, and type II diabetes. In addition, liver inflammation pushes the liver from non-alcoholic fatty liver disease (NAFLD) through non-alcoholic steatohepatitis (NASH - a form of hepatitis), and to cirrhosis and liver cancer. Every person has an internal body clock, or "circadian rhythm", which is built into every cell and helps the body function. There is new evidence of a circadian clock in the liver that controls fat metabolism. This offers a new perspective on how the progression of the above illnesses may be interrupted.Here, I will test the hypothesis that the circadian clock, and circadian metabolic circuits in the liver can be affected by nutrient supply, and I will further test the role of signal mediators (chemicals) linked to feeding, and energy metabolism, including ceramides (sphingolipids derived from the intestinal epithelium), and short-chain fatty acids (products of the intestinal microbiome - bacteria colony - with proposed liver regulating activity). I will use primary human liver cells to create liver "organoids" (microlivers) for these studies. In parallel I will use primary mouse liver cells, as these also offer the opportunity to use cells from genetically modified mice carrying circadian clock reporter genes, which I can track in real-time through multiple circadian cycles, and in addition I can selectively delete particular circadian clock components including the genes BMAL1 and REVERBa.I will go on to use this organoid system to investigate how targeting the circadian clock in the liver can regulate nutrient sensing, and handling of metabolites involved in energy conversion. In this way I can use small, drug-like molecules to regulate the clock (e.g. crytochrome activators, and REVERB ligands) along with the selective deletion of genes like BMAL1 (which stops the circadian clock), or REVERBa (which breaks the connection between the clock and the liver fat-production programme).I will identify how signals derived from feeding, including glucose, fatty acids, as well as signalling mediators including short chain fatty acids and ceramides, impact on the core liver clock, and affect the circadian clock controlled metabolic network. I will go on to discover how the operation of the clock impacts on handling of metabolic changes whereby glucose and fatty acids are subject to oxidation, or in the case of glucose to lipogenesis. I will have the opportunity to further test the integrity of this system in response to inflammatory signals such as those experienced by people with chronic inflammatory disease such as rheumatoid arthritis, or the chronic low-grade inflammation that is a consistent feature of obesity.