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Metabolism

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Articles 1 - 30 of 117

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige Apr 2019

Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige

Open Access Articles

Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise. Gene networks involved in vascularization were identified as prominent targets of exercise, which led us to investigate the vasculature architecture and endothelial phenotype. Vascular density in scWAT was found to be compromised in HFD, and exercise rescued this defect ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Jan 2019

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

Open Access Articles

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop ...


Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez Jan 2019

Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez

Publicly Accessible Penn Dissertations

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has a well-characterized role in the developmental process of adipogenesis and transcriptional regulation of lipid metabolism. However, its expression patterns and functions in various cancer subtypes are less understood. My studies investigate the role of PPARγ in two distinct cancers of the urinary tract: clear cell renal cell carcinoma (ccRCC) and bladder urothelial carcinoma (UC). In ccRCC, I hypothesized that PPARγ activity contributes to the aberrant lipid accumulation phenotype characteristic of this disease, thereby promoting tumor progression. Through ChIP-seq, I demonstrated that PPARγ and its heterodimeric DNA binding partner retinoid X receptor ...


The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Dwight Forshee Dec 2018

The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Dwight Forshee

ELAIA

The microbiome is a dynamic community that can positively and negatively influence host health. Lactobacillus reuteri is a probiotic that has received much attention for its ability to inhibit pathogens such as Salmonella typhimurium, Escherichia coli, and Clostridium difficile. It does so by its unique ability to metabolize glycerol into the antimicrobial compound 3-HPA, which is commonly referred to as reuterin. The ability to secrete reuterin is dependent not only on glycerol availability but also the concentration of glucose. In fact, there appears to be a “goldilocks” ratio between glucose and glycerol as either too much or too little glucose ...


The Multifaceted Roles Of Cd177 In Mammary Tissue Development And Breast Cancer, Paige Nicole Kluz Dec 2018

The Multifaceted Roles Of Cd177 In Mammary Tissue Development And Breast Cancer, Paige Nicole Kluz

Theses and Dissertations

Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, expression to be positively correlated with relapse-free (RFS), metastasis-free (MFS) or overall survival (OS) in several solid cancers including those from breast, prostate, cervix, and lung. To study the role of CD177 in breast cancer, we generated a total body Cd177 knockout mouse. These mice had no profound phenotype at 3 - months of age or younger. The only phenotype found at this age was reduced peripheral neutrophil counts, but no difference in their ability to clear ...


Mitochondrial Metabolism In Major Neurological Diseases, Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson, Ramon Sun Nov 2018

Mitochondrial Metabolism In Major Neurological Diseases, Zhengqiu Zhou, Grant L. Austin, Lyndsay E. A. Young, Lance A. Johnson, Ramon Sun

Molecular and Cellular Biochemistry Faculty Publications

Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation ...


Regulation Of Plasma Triglycerides By Angptl4 And Gpihbp1, Emily Malcolm Cushing Aug 2018

Regulation Of Plasma Triglycerides By Angptl4 And Gpihbp1, Emily Malcolm Cushing

Theses and Dissertations

The absorption, packaging, and delivery of fat to appropriate peripheral tissues is essential for maintaining metabolic homeostasis, and defects or dysregulation of these processes can contribute to metabolic disorders such as diabetes, obesity, and hyperlipidemia. In the intestine, dietary fat is packaged into triglyceride-rich lipoprotein particles and delivered to peripheral tissues through the circulatory system.

Lipolysis of lipoprotein triglycerides requires the enzyme lipoprotein lipase (LPL) and takes place on the luminal surface of capillary endothelial cells. Lipolysis by LPL is regulated in part by two proteins, GPIHBP1 and ANGPTL4. GPIHBP1, a GPI-anchored protein of capillary endothelial cells, is responsible for ...


The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Forshee May 2018

The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Forshee

Honors Program Projects

The microbiome is a dynamic community that can positively and negatively influence host health. Lactobacillus reuteri is a probiotic that has received much attention for its ability to inhibit pathogens such as Salmonella Typhimurium, Escherichia coli, and Clostridium difficile. It does so by its unique ability to metabolize glycerol into the antimicrobial compound 3-HPA, which is commonly referred to as reuterin. The ability to secrete reuterin is dependent not only on glycerol availability but also the concentration of glucose. In fact, there appears to be a “goldilocks” ratio between glucose and glycerol as either too much or too little glucose ...


The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Forshee Apr 2018

The Effects Of Inulin And Galactooligosaccharides On The Production Of Reuterin By Lactobacillus Reuteri, Micah Forshee

Scholar Week 2016 - present

The microbiome is a dynamic community that can positively and negatively influence host health. Lactobacillus reuteri is a probiotic that has received much attention for its ability to inhibit pathogens such as Salmonella Typhimurium, Escherichia coli, and Clostridium difficile. It does so by its unique ability to metabolize glycerol into the antimicrobial compound 3-HPA, which is commonly referred to as reuterin. The ability to secrete reuterin is dependent not only on glycerol availability but also the concentration of glucose. In fact, there appears to be a “goldilocks” ratio between glucose and glycerol as either too much or too little glucose ...


Identification And Characterization Of Regulators Of Glut4 Trafficking, Daniel Richard Gulbranson Feb 2018

Identification And Characterization Of Regulators Of Glut4 Trafficking, Daniel Richard Gulbranson

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Cargo proteins moving between organelles are transported by membrane-enclosed vesicles. Identifying the factors regulating vesicle-mediated transport remains a major challenge in mammalian cells. Here, we performed unbiased genome-wide CRISPR-Cas9 genetic screens to systematically dissect insulin-dependent translocation of glucose transporters (GLUTs), a classic vesicle transport pathway crucial to mammalian physiology. These screens identified known regulators of the pathway as well as a large number of unknown regulatory factors that we validated in secondary screens. The identified genes encode established or predicted factors involved in vesicle budding or fusion, cargo sorting, signal transduction, cell motility, and cellular metabolism, as well as proteins ...


Functions Of Maize Genes Encoding Pyruvate Phosphate Dikinase In Developing Endosperm, Ryan R. Lappe, John W. Baier, Susan K. Boehlein, Ryan Huffman, Qiaohui Lin, Fabrice Wattebled, A. Mark Settles, L. Curtis Hannah, Ljudmilla Borisjuk, Hardy Rolletschek, Jon D. Stewart, M. Paul Scott, Tracie A. Hennen-Bierwagen, Alan M. Myers Jan 2018

Functions Of Maize Genes Encoding Pyruvate Phosphate Dikinase In Developing Endosperm, Ryan R. Lappe, John W. Baier, Susan K. Boehlein, Ryan Huffman, Qiaohui Lin, Fabrice Wattebled, A. Mark Settles, L. Curtis Hannah, Ljudmilla Borisjuk, Hardy Rolletschek, Jon D. Stewart, M. Paul Scott, Tracie A. Hennen-Bierwagen, Alan M. Myers

Agronomy Publications

Maize opaque2 (o2) mutations are beneficial for endosperm nutritional quality but cause negative pleiotropic effects for reasons that are not fully understood. Direct targets of the bZIP transcriptional regulator encoded by o2 include pdk1 and pdk2 that specify pyruvate phosphate dikinase (PPDK). This enzyme reversibly converts AMP, pyrophosphate, and phosphoenolpyruvate to ATP, orthophosphate, and pyruvate and provides diverse functions in plants. This study addressed PPDK function in maize starchy endosperm where it is highly abundant during grain fill. pdk1 and pdk2 were inactivated individually by transposon insertions, and both genes were simultaneously targeted by endosperm-specific RNAi. pdk2 accounts for the ...


Skeletal Muscle Metabolism: From Tissue To Stem Cell, Katherine Elise Gadek Jan 2018

Skeletal Muscle Metabolism: From Tissue To Stem Cell, Katherine Elise Gadek

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Excessive circulating triglycerides due to reduction or loss of lipoprotein lipase (LPL) activity contribute to hypertriglyceridemia and increased risk for pancreatitis. The only gene therapy treatment for LPL deficiency decreases pancreatitis but minimally reduces hypertriglyceridemia. Synthesized in striated muscle and adipose tissue, LPL is then trafficked to blood vessel endothelial cells where it hydrolyzes triglycerides into free fatty acids. We conditionally knocked out LPL in differentiated striated muscle tissue lowering striated muscle LPL activity and causing hypertriglyceridemia. We crossed these LPL knockout mice with mice possessing a conditional avian retroviral receptor gene and infected mice with human LPL or mCherry ...


Investigating The Molecular Mechanism Of Glut4 Trafficking, Jessica Miller Jan 2018

Investigating The Molecular Mechanism Of Glut4 Trafficking, Jessica Miller

Undergraduate Honors Theses

The insulin-stimulated glucose transporter GLUT4 is essential to maintaining metabolic homeostasis in mammalian cells. Regulated trafficking of GLUT4 to and from the plasma membrane relies on a complex molecular mechanism integrating insulin signaling and vesicle transport. Understanding this pathway becomes increasingly crucial as Type II Diabetes, a disease characterized by insulin resistance, becomes more prevalent in the population. Despite decades of research, the molecular mechanism of GLUT4 trafficking is not yet fully understood. CRISPR-Cas9 allows for the ablation of individual genes so their role in GLUT4 trafficking can be investigated. A flow cytometry-based assay is used in this study to ...


Emergence Of New Metabolic Pathways In Escherichia Coli, Michael Kristofich Jan 2018

Emergence Of New Metabolic Pathways In Escherichia Coli, Michael Kristofich

Undergraduate Honors Theses

Catalytic promiscuity provides a starting point for the evolution of new enzymes. Taking this concept further, a series of promiscuous enzymes may assemble to form the basis of a new metabolic pathway (termed “serendipitous pathway”) that may emerge and become more efficient in adapting bacterial cells that require it to grow. The Copley lab at the University of Colorado at Boulder has been observing genetic changes that improve growth of Escherichia coli cells that lack the essential gene pdxB. These genetic changes are believed to improve the flux of metabolites through one or more serendipitous pathways that make up for ...


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O’Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O’Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

Molecular and Cellular Biochemistry Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Regulation Of Liver Mitochondrial Metabolism During Hibernation By Post-Translational Modification, Katherine E. Mathers Dec 2017

Regulation Of Liver Mitochondrial Metabolism During Hibernation By Post-Translational Modification, Katherine E. Mathers

Electronic Thesis and Dissertation Repository

Hibernation, characterized by a seasonal reduction in metabolism and body temperature, allows animals to conserve energy when environmental conditions (e.g. temperature, food availability) are unfavourable. During hibernation, small mammals such as the 13-lined ground squirrel (Ictidomys tridecemlineatus) cycle between two distinct metabolic states: torpor, where metabolic rate is suppressed by >95% and body temperature falls to ~5 °C, and interbout euthermia (IBE), where metabolic rate and body temperature rapidly increase and are maintained at euthermic levels several hours. Suppression of metabolism during entrance into torpor is paralleled by rapid suppression of liver mitochondrial metabolism. In my thesis, I aimed ...


Mitochondrial Reactive Oxygen Species In Lipotoxic Hearts Induces Post-Translational Modifications Of Akap121, Drp1 And Opa1 That Promote Mitochondrial Fission, Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose Mcglauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel Nov 2017

Mitochondrial Reactive Oxygen Species In Lipotoxic Hearts Induces Post-Translational Modifications Of Akap121, Drp1 And Opa1 That Promote Mitochondrial Fission, Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose Mcglauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel

Biochemistry -- Faculty Publications

Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood.

Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.

Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing long-chain acyl-CoA synthetase 1 in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation ...


Critical Role For Arginase 2 In Obesity-Associated Pancreatic Cancer, Tamara Zaytouni, Pei-Yun Tsai, Daniel S. Hitchcock, Cory D. Dubois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J. Lenehan, Brian M. Wolpin, Mari Mino-Kenudson, Eduardo M. Torres, Nicholas Stylopoulos, Clary B. Clish, Nada Y. Kalaany Aug 2017

Critical Role For Arginase 2 In Obesity-Associated Pancreatic Cancer, Tamara Zaytouni, Pei-Yun Tsai, Daniel S. Hitchcock, Cory D. Dubois, Elizaveta Freinkman, Lin Lin, Vicente Morales-Oyarvide, Patrick J. Lenehan, Brian M. Wolpin, Mari Mino-Kenudson, Eduardo M. Torres, Nicholas Stylopoulos, Clary B. Clish, Nada Y. Kalaany

UMass Metabolic Network Publications

Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of (15)N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of ...


Another Route For Amino Acid Production?: Reverse Genetic Probing For A Functional Cytosolic Shikimate Pathway In Plants, Gabrielle C. Buck, Joseph Lynch, Natalia Dudareva Aug 2017

Another Route For Amino Acid Production?: Reverse Genetic Probing For A Functional Cytosolic Shikimate Pathway In Plants, Gabrielle C. Buck, Joseph Lynch, Natalia Dudareva

The Summer Undergraduate Research Fellowship (SURF) Symposium

The shikimate pathway is a metabolic pathway that produces the three aromatic amino acids—phenylalanine, tryptophan, and tyrosine—which are essential to human diets and necessary for many plant functions. Consequently, the shikimate pathway is commonly targeted for antibiotic and herbicide strategies as well as genetic engineering in several fields. This pathway is known to be localized in the plastids, or double membrane-bound organelles, of plant cells; however, there is enzymatic evidence of another shikimate pathway in the cell fluid, or cytosol. To determine whether a complete cytosolic shikimate pathway exists, we used a modified gene for the first enzyme ...


Age-Associated Metabolic Reprogramming, Oxidative Stress Response, And Cancer Progression, Jyung Mean Son Aug 2017

Age-Associated Metabolic Reprogramming, Oxidative Stress Response, And Cancer Progression, Jyung Mean Son

Theses and Dissertations

Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigates whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were performed in quiescent NHFs from younger (newborn, 3-d, 5-m, and 1-y) and older (58-y, 61-y, 63-y, 68-y, and 70-y) donors as well as NHFs from the same individual at different ages (29-y, 36-y, and 46-y). Results show significant changes in cellular metabolism during ...


Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan Jun 2017

Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.


A Genetic Analysis Of Nuclear Functions Of The Lipin Protein In Drosophila Melanogaster, Xeniya Rudolf May 2017

A Genetic Analysis Of Nuclear Functions Of The Lipin Protein In Drosophila Melanogaster, Xeniya Rudolf

Theses and Dissertations

Lipins are a family of proteins that have critical functions in the control of fat storage and energy homeostasis. Biochemically, lipins have two functions. They provide an enzymatic activity (phosphatidate phosphatase or PAP activity) in the glycerol-3 phosphate pathway that leads to the production of storage fats (triacylglycerols). In addition, they play a role in the regulation of genes in the cell nucleus as transcriptional co-regulators. The PAP activity of lipins has been widely studied in a number of organisms. However, the transcriptional co-regulator function is not as well described in the literature. The transcriptional function of lipins depends on ...


Cytosolic Acetyl-Coa Promotes Histone H3 Lysine 27 Acetylation In Arabidopsis, Chen Chen Feb 2017

Cytosolic Acetyl-Coa Promotes Histone H3 Lysine 27 Acetylation In Arabidopsis, Chen Chen

Electronic Thesis and Dissertation Repository

Acetyl-coenzyme A (acetyl-CoA) serves as a central metabolite in energy metabolism and biosynthesis. High level of acetyl-CoA can fuel the tricarboxylic acid (TCA) cycle to generate energy and store excess energy in fatty acids. Meanwhile, it also provides acetyl groups for protein acetylation, which normally occurs at the lysine or arginine residues. Acetylation regulates protein functions largely due to the change of total charges. Acetylation of histones, for example, can lead to loss of the interaction between histone and DNA, thus relaxing chromatin structure and potentially promoting gene expression. However, whether and how acetyl-CoA regulates plant chromatin remains unexplored. Here ...


Therapeutic Exploitation Of Metabolic Checkpoints In Cancer Cells, Deven S. Patel Feb 2017

Therapeutic Exploitation Of Metabolic Checkpoints In Cancer Cells, Deven S. Patel

All Dissertations, Theses, and Capstone Projects

During the G1 phase of the cell cycle, normal cells respond to growth factors and nutrients prior to entering S-phase to replicate its genome. We previously reported that the growth factor-mediated restriction point is distinguishable from a series of late G1 metabolic checkpoints mediated by essential amino acids (EAAs), the conditionally essential amino acid glutamine (Gln), and mTOR – the mammalian target of rapamycin. Mutations in genes encoding proteins that regulate G1 cell cycle progression are observed in virtually all cancers. We observed that cancer cells with K-Ras mutations bypass the late G1 Gln checkpoint when deprived of Gln and instead ...


Lipid Sensing By Mammalian Target Of Rapamycin, Deepak Menon Feb 2017

Lipid Sensing By Mammalian Target Of Rapamycin, Deepak Menon

All Dissertations, Theses, and Capstone Projects

Mammalian target of Rapamycin (mTOR) is a protein kinase that integrates nutrient and growth factor signals to promote cellular growth and proliferation. mTOR exists in two complexes - mTORC1 and mTORC2 that are distinguished by their binding partners and signaling inputs. mTORC1 is responsive to growth factors, amino acids and glucose and is associated with Raptor; whereas, mTORC2 is responsive primarily to growth factors and is associated with Rictor. Raptor and Rictor confer substrate specificity to mTORC1 and mTORC2 respectively. Phosphatidic acid (PA), a lipid second messenger and a central metabolite for membrane phospholipid biosynthesis, is required for the stability and ...


Identification And Characterization Of Regulators Of Glut4 Trafficking, Daniel Richard Gulbranson Jan 2017

Identification And Characterization Of Regulators Of Glut4 Trafficking, Daniel Richard Gulbranson

Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations

Cargo proteins moving between organelles are transported by membrane-enclosed vesicles. Identifying the factors regulating vesicle-mediated transport remains a major challenge in mammalian cells. Here, we performed unbiased genome-wide CRISPR-Cas9 genetic screens to systematically dissect insulin-dependent translocation of glucose transporters (GLUTs), a classic vesicle transport pathway crucial to mammalian physiology. These screens identified known regulators of the pathway as well as a large number of unknown regulatory factors that we validated in secondary screens. The identified genes encode established or predicted factors involved in vesicle budding or fusion, cargo sorting, signal transduction, cell motility, and cellular metabolism, as well as proteins ...


Histone Deacetylase 3 And The Epigenomic Regulation Of Brown Adipose Physiology, Matthew Joseph Emmett Jan 2017

Histone Deacetylase 3 And The Epigenomic Regulation Of Brown Adipose Physiology, Matthew Joseph Emmett

Publicly Accessible Penn Dissertations

Brown adipose tissue (BAT) is a thermogenic organ, which helps to protect body temperature against cold and can counteract metabolic disease. Numerous pathways modulate the activity of BAT in a highly regulated and coordinated manner to exert tight control over its immense calorie burning capacity. However, less is known regarding the transcriptional and epigenomic mechanisms controlling the thermogenic gene program of brown adipocytes. Here, we show that histone deacetylase 3 (HDAC3) is required for the activation of BAT enhancers to ensure thermogenic aptitude, thus enabling survival of dangerously cold environmental temperature. Loss of HDAC3 leads to deficient expression of uncoupling ...


Functions Of Maize Genes Encoding Pyruvate Orthophosphate Dikinase In Developing Maize Endosperm And Their Enzymatic Properties, Ryan R. Lappe Jan 2017

Functions Of Maize Genes Encoding Pyruvate Orthophosphate Dikinase In Developing Maize Endosperm And Their Enzymatic Properties, Ryan R. Lappe

Graduate Theses and Dissertations

The research described herein, focuses on investigating the role of pyruvate phosphate dikinase (PPDK) and factors influencing its activity in maize starchy endosperm (SE) tissue. PPDK reversibly converts phosphoenolpyruvate (PEP), pyrophosphate (PPi), and AMP, to pyruvate, phosphate (Pi), and ATP. PPDK is found in microorganisms and plant tissues with diverse functions. PPDK is abundant in maize SE during grain fill, but little is known about its role. Hypotheses were tested using transposon-insertion alleles affecting individual genes and by eliminating all PPDK expression using RNAi. PPDK's C4 metabolism function in mesophyll was proven to be essential in maize. RNAi transgenes ...


Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim Dec 2016

Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim

UMass Metabolic Network Publications

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates ...