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

肥胖是一种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，这可能导致功能异常，包括胰岛素抵抗和II型糖尿病。此外，肝脏炎症将肝脏从非酒精性脂肪性肝病（NAFLD）推动到非酒精性脂肪性肝炎（NASH -肝炎的一种形式），以及肝硬化和肝癌。每个人都有一个内部生物钟，或“昼夜节律”，它内置于每个细胞中，有助于身体功能。有新的证据表明，肝脏中的生物钟控制着脂肪代谢。这为如何阻断上述疾病的进展提供了一个新的视角。在这里，我将检验生物钟和肝脏中的昼夜代谢回路可以受到营养供应影响的假设，我将进一步检验信号介质的作用（化学品）与喂养和能量代谢有关，包括神经酰胺（源自肠上皮的鞘脂）和短链脂肪酸（肠微生物组的产物-细菌菌落-具有拟议的肝脏调节活性）。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）。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细胞的机会，我可以通过多个昼夜节律周期实时跟踪，此外，我可以选择性地删除特定的生物钟组件，包括基因BMAL 1和REVERBa。我将继续使用这个类器官系统来研究如何在体内靶向生物钟。肝脏可以调节营养物的感知和参与能量转换的代谢物的处理。这样我就可以用类似药物的小分子来调节生物钟（例如低温色素激活剂和REVERB配体）沿着选择性缺失基因如BMAL 1（停止生物钟），或REVERBa（这打破了生物钟和肝脏脂肪生产程序之间的联系）。我将确定如何从进食中获得信号，包括葡萄糖，脂肪酸，以及包括短链脂肪酸和神经酰胺的信号传导介质，影响核心肝脏时钟，并影响生物钟控制的代谢网络。我将继续发现生物钟的运作如何影响代谢变化的处理，从而葡萄糖和脂肪酸受到氧化，或在葡萄糖的情况下脂肪生成。我将有机会进一步测试该系统对炎症信号的反应的完整性，例如患有慢性炎症性疾病（如类风湿性关节炎）或慢性低度炎症（肥胖的一贯特征）的人所经历的炎症信号。

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.