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

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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.