Day 2 :
Keynote Forum
Philipp Kaldis
National University of Singapore, Singapore
Keynote: Metabolic rewiring during liver regeneration
Biography:
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.
Abstract:
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.
Keynote Forum
Walter Wahli
Nanyang Technological University, Singapore
Keynote: PPARα in hepatocytes integrates microbiome-derived signals and is protective against fatty liver in both neonate and adult mice
Biography:
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.
Abstract:
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.
- Metabolomic Profiling | Metabolomics in Precision Medicine | Frontiers of Metabolomics Research
Session Introduction
Zhi Yang Tam
Singapore Phenome Center, Singapore
Title: Metabolite profiling in identifying metabolic biomarkers in older people with late-onset diabetes mellitus
Biography:
Zhi Yang Tam is a Computational Biologist with experience in applying supervised and unsupervised machine learning methodology on high throughput and imaging data, modeling biological processes using deterministic and stochastic models and applying other statistical tools to derive insights into biological process.
Abstract:
Regulation of blood glucose in the body requires precise coordination between different endocrine organs. Diabetes mellitus arises from a dysregulated response to elevated glucose levels in the circulation. Globally, the prevalence of diabetes has increased dramatically in all age groups. Diabetes in older adults is associated with higher mortality and reduced functional status, leading to higher rate of institutionalization. Despite the potential healthcare challenges associated with the presence of diabetes in the older population, the pathogenesis and phenotype of late-onset diabetes is not well studied. Here we applied untargeted metabolite profiling of urine samples from people with and without late-onset diabetes using ultra-performance liquid-chromatography mass-spectrometry (UPLC-MS) to characterize the urine metabolic profile for the identification of urinary biomarkers for late-onset diabetes in older individuals. Statistical modeling of measurements and thorough validation of structural assignment using liquid chromatography tandem mass-spectrometry (LC-MS/MS) have led to the identification of metabolite biomarkers associated with late-onset diabetes mellitus. Lower levels of phenylalanine, acetylhistidine, and cyclic adenosine monophosphate (cAMP) were found in urine samples of diabetes subjects validated with commercial standards. Elevated level of 5'-methylthioadenosine (MTA) that previously has only been implicated in animal model of diabetes, was found in urine of older people with diabetes.
Kambiz Gilany
Avicenna Research Institute, Iran
Title: Metabolomics study of human seminal plasma of infertile male
Biography:
Abstract:
Statement of the Problem: About 15% couples are infertile. The “male factor” contributes to half of infertility. In spite of the development of treatment for infertile men, many questions regarding etiology of the male infertility remain to be answered. The use of high-throughput techniques brings hopes to treatment of male infertility. Especially, at present, metabolomics studies have been recognized as an outlook for the systematization of specific biomarkers in approval of a better identification of male infertility. Human semen is a biological fluid that consists of spermatozoa and seminal plasma. The seminal plasma can be used as an excellent source for noninvasive detection and diagnostic test of the male infertility. We have used the seminal plasma for metabolomics studies as a screening tool to diagnose male infertility and for biomarker discovery.
Methodology & Theoretical Orientation: There are different approaches that can be used in metabolomics study. We have used the easiest and cheapest approaches for clinical diagnosis, the pattern-recognition methods using Raman spectrometry. Additionally, we have applied GC-MS/MS for biomarker discovery.
Findings: Using metabolomics fingerprinting, we were able to classify idiopathic infertile men and asthenozoospermia men in the different groups compared to the fertile men. Additionally, it was observed at metabolome level that, there was oxidative imbalance in the seminal plasma of these patients. Via metabolomics profiling, we showed that metabolome of the seminal plasma of the non-obstructive azoospermia patients can be used for detection of spermatogenesis, as a noninvasive technique. Furthermore, we identified 38 metabolites which showed deregulation in these patients and can be used as potential biomarker for detection of spermatogenesis.
Conclusion & Significance: We have shown that metabolomics study of infertile men have come successfully out of discovery phase using the biological material seminal plasma. We now need to go to the test validation stage for further development of the technology.
Binh Thang Tran
National Cancer Center Graduate School of Cancer Science and Policy, South Korea
Title: Metabolic syndrome: Evidences from the Korean National Health and Nutrition Examination Survey
Biography:
Binh Thang Tran is currently a Graduate student in the National Cancer Center Graduate School of Cancer Science and Policy, South Korea. He has also formerly worked for Hue University of Medicine and Pharmacy, Hue city, Vietnam, as a Research Associate for 5 years. His research interests focus on the health evaluation and cancer prevention.
Abstract:
Metabolic syndrome (MS) prevalence in Korea increased between the mid-1990s and mid-2000s; however, no data on the recent trends of MS prevalence are available. Furthermore, the Korean Government and the Korean National Assembly approved laws on health promotion and disease prevention, and one of the main targets of Health Plan 2020 is to reduce smoking, alcohol drinking and obesity. This policy includes lifestyle interventions, food safety and public education about healthy eating behaviors and physical activity. Therefore, a study is needed as a part of evaluation of the effectiveness of this intervention. We carried out the study using data from the Korean National Health and Nutrition Examination Survey from 2008 to 2013 to determine the prevalence trend of MS and risk factors. The revised National Cholesterol Education Program criteria were used for defining MS. A total of 34,587 men and women were included in the analysis. We found that MS prevalence in Korea is high, but did not follow a significant trend during 2008-2013. Several factors contributed to the stable MS prevalence: On the one hand, increased prevalence of high FPG, high BP, calorie intake and physical inactivity and on the other hand, decreased prevalence of abdominal obesity and smoking. Greater awareness of MS and its health consequences can help optimize the treatment of risk factors. Furthermore, risk factors such as smoking, alcohol drinking, obesity, diet and physical inactivity need to be considered in public health interventions. A multidimensional approach is vital to prevent future increases in MS.
Biography:
Amar Mohamed Ismail is head Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, Al-Neelain University – Sudan. Amar has his expertise in endocrinology and metabolism especially in breast cancer cells. In this work we aimed to investigate whether extra virgin olive oil and oleic acid could enhance the effects of aromatase inhibitors (letrozole and anastrozole) in estrogen receptor-positive MCF-7 cells, as well as to investigate its influence on cholesterol pathway.
Abstract:
Background: Olive oil and cancer relationship has been proved by the support of many evidences. Present study aim to investigate whether EVOO and Oleic acid (OA) could enhance the effects of aromatase inhibitors (Letrozole and Anastrozole) in MCF-7 cells as well as to investigate its influence on aromatization.
Materials and Methods: The viability of the cells was assessed by MTT test. MCF-7 cells were divided into seven groups as flows: Letrozole treated, Anastrozole treated, Anastrozole combined with EVOO, Letrozole combined with EVOO, Anastrozole combined with OA, Letrozole combined with OA and control group. Estrone and cholesterol lysates were measured.
Results: MTT test results showed that for both Letrozole and Anastrozole combination with (EVOO or OA) significantly decreases the viability of the cells in comparison of standalone Anastrozol and Letrozol. Letrozole and Anastrozole treatments significantly increase the levels of cholesterol in comparison with the control, while combination treatments showed significant decreases in cholesterol levels. Standalone Letrozole or Anastrozole treatment significantly decreased estrone level while combination treatment highly significantly decreases the level of Estrone. Significance was determined according to p-value <0.05.
Conclusion: EVOO and OA potentiate aromatase inhibitors action lowering of Cholesterol, which acts as a precursor for estrogens hormones and cholesterol metabolites biosynthesis hence preventing MCF-7 cells proliferation.
Sayan Chakraborty
Institute of Molecular and Cell Biology – A Star, Singapore
Title: An oncogenic role of Agrin in hepatocellular carcinoma: Mechanisms and therapeutic strategies of targeting Agrin in cancer
Biography:
Sayan Chakraborty has obtained his PhD from the Chicago Medical School, USA in Molecular Virology, where he deciphered the mechanisms of entry and infection of Kaposi’s sarcoma herpesvirus in endothelial cell sarcoma. Subsequently, he moved to IMCB, Singapore to pursue research in hepatocellular carcinoma. Presently, he is working as a Senior Researcher in IMCB and he has identified Agrin as a promising therapeutic target for liver cancer.
Abstract:
Problem: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related deaths globally. The identity and role of cell surface molecules driving complex biological events leading to HCC progression are poorly understood, hence representing major lacunae in HCC therapies.
Approach: Combining quantitative proteomics and biochemical approaches, we uncover a critical oncogenic role of Agrin, which is frequently overexpressed and secreted in HCC. Our systematic cell biological analysis indicated a role of Agrin in maintaining focal adhesion integrity through stimulation of Focal Adhesion Kinase (FAK) that functions in cellular migration, invasion and tumor growth. However, the exact mechanisms by which Agrin’s mediates liver tumorigenesis remain unknown.
Findings: The present study dissects how Agrin mediated signals from the extracellular matrix are sensed by tumor cells. Agrin binds to its co-receptors Lrp4 and subsequently activates MuSK to mediate oncogenic effects through activating focal adhesions. Additionally, integrins and focal adhesions collaborate closely with Agrin in communicating ECM signals to intracellular components in HCC cell lines, thereby promoting their invasive, migratory and growth capabilities. More importantly, Lrp4-MuSK as well as integrin-FAK pathways are crucial downstream signaling axes of Agrin’s functions in liver tumorigenesis. Additional studies reveal that Agrin activates the Yes-Associated Protein (YAP) oncogenic program in liver by negatively regulating Hippo tumor suppressor pathway.
Conclusion & Significance: Our evidence suggests that function blocking antibodies against Agrin may inhibit integrin-FAK and YAP signaling, thereby reducing in vivo tumorigenesis. In addition to FAK and YAP inhibition in HCC, these novel insights shed significant weight on the possibility of targeting Agrin mediated oncogenesis in HCC.
- Special Session
Session Introduction
Jaleel k Ahmed
Babylon University, Iraq
Title: Anthocyanin Acts As Scavenger For Heavy Metal Ions, Attack Cancer cell and Interacts With Uric Acid And Urea To Expel it Through Urine System
Biography:
Jaleel K Ahmed has his expertise in Iron and Steel Industry. He has used chlorophyll as gamma ray absorber to protect Iraqi children from cancer and used red beet juice as scavenger for poisonous heavy metal ions and anticancer and detoxification of urea and uric acid from human body via urine system.
Abstract:
Anthocyanin from red beet juice, cherry and red rose which is extracted mechanically is water soluble due to the many hydroxyl groups and glucose molecule which is carried on the anthocyanin (position 3 on it). This juice is slightly sweet due to the free sugar present. The juice is very slightly acidic due to its exchangeable proton (Transmembrane proton with radius 1.5×10-6 nm). The concentration of the proton in the juice is 10-6.4 g proton/L. In spite of very low concentration of the exchangeable proton in the juice, it is very active to attack metal ions as soon as it comes in contact with it and as well as hetero atoms (like O, N, S) in organic molecules, such process is called protonation (exothermic process) in which this process pull the abnormal high energy molecules downhill and stabilize it. Proton is condensed in aqueous solution called hydrated proton PH2O which moves to the whole human body and when become near high energy molecule with hetero atom leaving the water and attacks that molecule similar to the aircraft carrier when becomes near to the target, the aircraft leaves the carrier and attacks the target. In such process, proton saves the energy for the attack. Results show that solid anthocyanin from the evaporation of juice goes into condensation polymerization around 80 °C with liberation of water, as well as boiling concentrated juice (home-made) resulted in polymerization with very fine solid particles which reduce the ability of the exchangeable proton to precipitate heavy metal ions. Ultra violet-visible spectrum shows great difference between normal and filtered boiled juice .Thus it prefers to extract the juice mechanically not thermally and not any additional material added to the juice. Spectroscopic tests in addition to the visual one show that there is an interaction between anthocyanin and uric acid and urea in blood through hydrogen bonds and this help in detoxification process through urine system and this help kidney in its work.