Day 2 :
National University of Singapore, Singapore
Philipp Kaldis has received his PhD from the Institute for Cell Biology, ETH (Swiss Federal Institute of Technology), Zürich, Switzerland, where he worked on the mitochondrial creatine kinase with Dr. Theo Wallimann and Dr. Hans Eppenberger. He has then joined Dr. Mark Solomon’s Laboratory at Yale University School of Medicine, Department of Molecular Biophysics and Biochemistry, New Haven, Connecticut, as a Postdoctoral Fellow/Associate Research Scientist to investigate the activation of cyclin-dependent kinases (Cdks). He has later joined the NCI-Frederick as Tenure-Track Investigator and was promoted to Senior Investigator with tenure in 2006. In 2007, he has joined the IMCB as a Senior Principal Investigator. His main research interests are cell cycle, cancer, metabolism, liver regeneration and cancer.
Failure of tissue repair and regeneration in patients with liver disease is life threatening. During hepatic regeneration, there is a connection between cell division and metabolism. This is exacerbated in cases with metabolic disorders, where recovery from liver resection is impaired. However, the cross-talk between cell metabolism and division in the liver during response to injury is ill defined. To understand this association, we used integrative analysis of transcriptomic and metabolomic data in combination with advanced molecular imaging. We 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). Our results demonstrate that cell division is essential to maintain metabolic homeostasis in the liver and highlight the capacity of adaptation of metabolic flux in response to injury. These findings shed new light on the use of high-throughput data combined with molecular imaging to study metabolism during liver regeneration, offering new approaches to improve therapy and discovery of biomarkers potentially used in personalized medicine.
Nanyang Technological University, Singapore
Walter Wahli is a Professor of Metabolic Disease at Lee Kong Chian School of Medicine, Nanyang Technological University & Imperial College London, Singapore. He is also the President of the Council of the Nestle Foundation for the Study of Problems of Nutrition in the World. Prior to these appointments, he has spent most of his scientific career at the University of Lausanne, Switzerland. He was awarded several prizes and recently received the Lifetime Achievement Award from the Faculty of Biology and Medicine, University of Lausanne.
The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Germ-free mice display altered daily oscillation of clock gene expression with a change in the expression of clock output regulators. These alterations in microbiome-sensitive gene expression are associated with daily alterations in lipid, glucose and xenobiotic metabolism as revealed by hepatic metabolome analyses. Hepatic lipid catabolism is essential for the newborns to use milk fat as an energy source. PPARα in hepatocytes is critical for this function. PPARα expression is stimulated a few days before birth, which prepares the receptor for its physiological role in harnessing milk lipids after birth. This mechanism involves a fetal glucocorticoid receptor (GR)-PPARα axis in which GR directly binds to the Pparα promoter to stimulate its activity. In turn, under the control of PPARα, the expression of genes required for lipid catabolism is enhanced before birth so that the neonatal liver has a prompt capacity to extract energy from milk upon suckling. Interestingly, the PPARα target gene Fgf21 is not stimulated in the fetal liver and responds to PPARα only after birth following an epigenetic switch triggered by β-hydroxybutyrate-mediated inhibition of histone deacetylase 3. This study unveiled an endocrine axis in which fetal GR stimulates the expression of PPARα in anticipation of the shift in postnatal nutrient source. In adult mice, liver-specific deletion of PPARα impairs fatty acid homeostasis in the context of induced steatosis. It occurs without obesity and hyperglycemia. Therefore, liver-specific deletion of PPARα dissociates steatosis from obesity and type-2 diabetes. Altogether these findings underscore the relevance of hepatic PPARα as a drug target for NAFLDs as they show that PPARα plays a central role in the clearance of free fatty acids released from adipocytes, the major source of lipid that accumulate in NAFLD.