Thesis title: ANALYSIS OF METABOLISM DURING LIVER REGENERATION
Supervisor: Philipp KALDIS
Liver is one of the biggest solid organs in mammalian. Functioning as a metabolic center, it is the responsible to process nutrients and to regulate metabolism of glucose, fatty acids, and proteins. During the last decades, the number of patients presenting metabolic disorders has increased exponentially, correlated with the dramatic increased in morbidity and mortality of hepato-biliary-related diseases. The incidence of liver-related conditions has positioned liver cancer as one of the leading cancer mortality causes. Unfortunately, these days the most effective approach to treat liver diseases is liver resection or transplantation that mostly rely on the capacity of liver to regenerate. Since liver resection and/or transplantation are the first line of therapy offered to patients with liver disorders, understanding the mechanism by which the liver regenerates in normal and diseased conditions is of major interest. However, it has been shown that liver regeneration may be impaired in liver disease, especially when the liver suffers from impaired glucose or fatty acid metabolism. Therefore, my work is focused on studying changes in metabolism during liver regeneration when cellular division is impaired. I uncovered that when cell division is blocked, hepatic regeneration after acute liver damage is delayed with a concomitant shift from carbohydrate to amino acid metabolism. These changes are driven by impaired mitochondria oxidation and respiration, together with profound remodeling of the pyruvate flux resulting in increased activity of alanine transaminase (ALT). My results suggest that cell division is essential to maintain metabolic homeostasis. At the same time, these observations highlight the capacity of adaptation of the metabolic flux in response to injury. My findings shed new light on the use of high-throughput data combined with new and promising imaging approaches to study metabolism during liver regeneration, offering new approaches to discover biomarkers potentially used in personalized medicine.
It turned out that my PhD training was a personal fulfilling experience. Although the schedule during the first year was very tight due to the courses I had to attend in NUS, the knowledge acquired from the lecturers at NUS was helpful to solidify the base for my research project. During the following years, working under supervision of Philipp, I was able to obtain really good results as well as strengthen my relationship with my supervisor. Philipp has been supporting me, by giving me independence as well as a generous space to conduct my project. Moreover, I could work in close collaboration with many researchers from different institutes from Singapore and overseas, which helped me to improve my scientific skills. Furthermore, the lab is a very international - an environment that helped me to cultivate strong soft skills, such as improving my ability to communicate. I would like to thank all of my lab mates for helpful discussions, as well as all of the researchers in IMCB that I have interacted with. I would like to thank A*STAR, specially the SINGA office, for demonstrating confidence in me by providing a fellowship to do my research. I finally would like to thank the whole science community of Singapore that trusted me by giving me the opportunity to contribute to the local research landscape.
Figure legend: Hyperpolarized 13C-pyruvate flux revealed changes in pyruvate flux during liver regeneration with hepatic deletion of Cdk1.
In order to study the metabolic remodeling of hepatocytes during liver regeneration, whole metabolomics and transcriptomic analysis was performed in combination with advanced molecular imaging, suggesting that deletion of Cdk1 leads to a shift from carbohydrate to amino acid metabolism during liver regeneration.
Combined integrative metabolomics and transcriptomic analysis with advanced molecular imaging is shown at 8h (A), 36h (B), and 1 week (C) after PHx, respectively.
Pklr- Pyruvate kinase liver and red blood cells; ALT-Alanine transaminase; AST- Aspartate aminotransferase; LDH- Lactate dehydrogenase; PDH- Pyruvate dehydrogenase; PC- Pyruvate carboxylase.
For more information on Philipp KALDIS's lab, please click here.