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Articles 1 - 30 of 49

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

Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers Dec 2017

Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

Recent structural studies suggest that glucose transporter 1 (GLUT1)-mediated sugar transport is mediated by an alternating access transporter that successively presents exofacial (e2) and endofacial (e1) substrate-binding sites. Transport studies, however, indicate multiple, interacting (allosteric), and co-existent, exo- and endofacial GLUT1 ligand-binding sites. The present study asks whether these contradictory conclusions result from systematic analytical error or reveal a more fundamental relationship between transporter structure and function. Here, homology modeling supported the alternating access transporter model for sugar transport by confirming at least four GLUT1 conformations, the so-called outward, outward-occluded, inward-occluded, and inward GLUT1 conformations. Results from docking analysis ...


The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio Dec 2017

The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio

UMass Metabolic Network Publications

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an ...


Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano Dec 2017

Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano

UMass Metabolic Network Publications

The commitment to and execution of differentiation programmes involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The ...


Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis Nov 2017

Jnk Promotes Epithelial Cell Anoikis By Transcriptional And Post-Translational Regulation Of Bh3-Only Proteins, Nomeda Girnius, Roger J. Davis

UMass Metabolic Network Publications

Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here, we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that ...


Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein Nov 2017

Bivalent Epigenetic Control Of Oncofetal Gene Expression In Cancer, Sayyed K. Zaidi, Seth E. Frietze, Jonathan A. Gordon, Jessica L. Heath, Terri Messier, Deli Hong, Joseph R. Boyd, Mingu Kang, Anthony N. Imbalzano, Jane B. Lian, Janet L. Stein, Gary S. Stein

UMass Metabolic Network Publications

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency ...


Casein Kinase 2-Mediated Phosphorylation Of Brahma-Related Gene 1 Controls Myoblast Proliferation And Contributes To Swi/Snf Complex Composition, Teresita Padilla-Benavides, Brian T. Nasipak, Amanda L. Paskavitz, Dominic T. Haokip, Jake M. Schnabl, Jeffrey A. Nickerson, Anthony N. Imbalzano Nov 2017

Casein Kinase 2-Mediated Phosphorylation Of Brahma-Related Gene 1 Controls Myoblast Proliferation And Contributes To Swi/Snf Complex Composition, Teresita Padilla-Benavides, Brian T. Nasipak, Amanda L. Paskavitz, Dominic T. Haokip, Jake M. Schnabl, Jeffrey A. Nickerson, Anthony N. Imbalzano

UMass Metabolic Network Publications

Transcriptional regulation is modulated in part by chromatin-remodeling enzymes that control gene accessibility by altering chromatin compaction or nucleosome positioning. Brahma-related gene 1 (Brg1), a catalytic subunit of the mammalian SWI/SNF chromatin-remodeling enzymes, is required for both myoblast proliferation and differentiation, and the control of Brg1 phosphorylation by calcineurin, PKCbeta1, and p38 regulates the transition to differentiation. However, we hypothesized that Brg1 activity might be regulated by additional kinases. Here, we report that Brg1 is also a target of casein kinase 2 (CK2), a serine/threonine kinase, in proliferating myoblasts. We found that CK2 interacts with Brg1, and mutation ...


Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto Nov 2017

Mitochondrial Stress Restores The Heat Shock Response And Prevents Proteostasis Collapse During Aging, Johnathan Labbadia, Renee M. Brielmann, Mario F. Neto, Yi-Fan Lin, Cole M. Haynes, Richard I. Morimoto

UMass Metabolic Network Publications

In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target ...


Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos Nov 2017

Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos

UMass Metabolic Network Publications

OBJECTIVE: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types ...


Association Of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study, Ravi V. Shah, Ashish S. Yeri, Venkatesh L. Murthy, Joe M. Massaro, Ralph Sr. D'Agostino, Jane E. Freedman, Michelle T. Long, Caroline S. Fox, Saumya Das, Emelia J. Benjamin, Ramachandran S. Vasan, Christopher J. O'Donnell, Udo Hoffmann Nov 2017

Association Of Multiorgan Computed Tomographic Phenomap With Adverse Cardiovascular Health Outcomes: The Framingham Heart Study, Ravi V. Shah, Ashish S. Yeri, Venkatesh L. Murthy, Joe M. Massaro, Ralph Sr. D'Agostino, Jane E. Freedman, Michelle T. Long, Caroline S. Fox, Saumya Das, Emelia J. Benjamin, Ramachandran S. Vasan, Christopher J. O'Donnell, Udo Hoffmann

UMass Metabolic Network Publications

Importance: Increased ability to quantify anatomical phenotypes across multiple organs provides the opportunity to assess their cumulative ability to identify individuals at greatest susceptibility for adverse outcomes.

Objective: To apply unsupervised machine learning to define the distribution and prognostic importance of computed tomography-based multiorgan phenotypes associated with adverse health outcomes.

Design, Setting, and Participants: This asymptomatic community-based cohort study included 2924 Framingham Heart Study participants between July 2002 and April 2005 undergoing computed tomographic imaging of the chest and abdomen. Participants are from the offspring and third-generation cohorts.

Exposures: Eleven computed tomography-based measures of valvular/vascular calcification, adiposity, and muscle ...


Hdac3 Regulates Lymphovenous And Lymphatic Valve Formation, Harish P. Janardhan, Zachary J. Milstone, Masahiro Shin, Nathan D. Lawson, John F. Keaney Jr., Chinmay M. Trivedi Nov 2017

Hdac3 Regulates Lymphovenous And Lymphatic Valve Formation, Harish P. Janardhan, Zachary J. Milstone, Masahiro Shin, Nathan D. Lawson, John F. Keaney Jr., Chinmay M. Trivedi

UMass Metabolic Network Publications

Lymphedema, the most common lymphatic anomaly, involves defective lymphatic valve development; yet the epigenetic modifiers underlying lymphatic valve morphogenesis remain elusive. Here, we showed that during mouse development, the histone-modifying enzyme histone deacetylase 3 (Hdac3) regulates the formation of both lymphovenous valves, which maintain the separation of the blood and lymphatic vascular systems, and the lymphatic valves. Endothelium-specific ablation of Hdac3 in mice led to blood-filled lymphatic vessels, edema, defective lymphovenous valve morphogenesis, improper lymphatic drainage, defective lymphatic valve maturation, and complete lethality. Hdac3-deficient lymphovenous valves and lymphatic vessels exhibited reduced expression of the transcription factor Gata2 and its target ...


Role Of Granulocyte-Macrophage Colony-Stimulating Factor Production By T Cells During Mycobacterium Tuberculosis Infection, Alissa C. Rothchild, Britni L. Stowell, Girija Goyal, Claudio Nunes-Alves, Qianting Yang, Kadamba Papavinasasundaram, Christopher M. Sassetti, Glenn Dranoff, Xinchun Chen, Jinhee Lee, Samuel M. Behar Oct 2017

Role Of Granulocyte-Macrophage Colony-Stimulating Factor Production By T Cells During Mycobacterium Tuberculosis Infection, Alissa C. Rothchild, Britni L. Stowell, Girija Goyal, Claudio Nunes-Alves, Qianting Yang, Kadamba Papavinasasundaram, Christopher M. Sassetti, Glenn Dranoff, Xinchun Chen, Jinhee Lee, Samuel M. Behar

UMass Metabolic Network Publications

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF(-/-)) are highly susceptible to infection with Mycobacterium tuberculosis, and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T ...


Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy Oct 2017

Age-Associated Microrna Expression In Human Peripheral Blood Is Associated With All-Cause Mortality And Age-Related Traits, Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy

UMass Metabolic Network Publications

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 x 10(-4) (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Deltaage) and found that Deltaage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 x 10(-5) adjusted for sex and chronological age). Additionally, Deltaage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases. Wiley and Sons Ltd.


A Protein Scaffold Coordinates Src-Mediated Jnk Activation In Response To Metabolic Stress, Shashi Kant, Claire L. Standen, Caroline Morel, Dae Young Jung, Jason K. Kim, Wojciech Swat, Richard A. Flavell, Roger J. Davis Sep 2017

A Protein Scaffold Coordinates Src-Mediated Jnk Activation In Response To Metabolic Stress, Shashi Kant, Claire L. Standen, Caroline Morel, Dae Young Jung, Jason K. Kim, Wojciech Swat, Richard A. Flavell, Roger J. Davis

UMass Metabolic Network Publications

Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV. These interactions are required for SRC-induced activation ...


A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Caitlin M. Connolly, Hsin-Jung Chou, Yuanyuan Chen, Upasna Sharma, Hsuiyi V. Chen, Vineeta Bajaj, Daniel Na. Bolon, Oliver J. Rando, Paul D. Kaufman Sep 2017

A Synthetic Biology Approach To Probing Nucleosome Symmetry, Yuichi Ichikawa, Caitlin M. Connolly, Hsin-Jung Chou, Yuanyuan Chen, Upasna Sharma, Hsuiyi V. Chen, Vineeta Bajaj, Daniel Na. Bolon, Oliver J. Rando, Paul D. Kaufman

UMass Metabolic Network Publications

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this ...


A Dual Role Of Caspase-8 In Triggering And Sensing Proliferation-Associated Dna Damage, A Key Determinant Of Liver Cancer Development, Yannick Boege, Roger J. Davis, Achim Weber Sep 2017

A Dual Role Of Caspase-8 In Triggering And Sensing Proliferation-Associated Dna Damage, A Key Determinant Of Liver Cancer Development, Yannick Boege, Roger J. Davis, Achim Weber

UMass Metabolic Network Publications

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in ...


The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino Aug 2017

The Mitochondrial Unfolded Protein Response: Signaling From The Powerhouse, Mohammed A. Qureshi, Cole M. Haynes, Mark W. Pellegrino

UMass Metabolic Network Publications

Mitochondria are multifaceted and indispensable organelles required for cell performance. Accordingly, dysfunction to mitochondria can result in cellular decline and possibly the onset of disease. Cells use a variety of means to recover mitochondria and restore homeostasis, including the activation of retrograde pathways such as the mitochondrial unfolded protein response (UPRmt). In this Minireview, we will discuss how cells adapt to mitochondrial stress through UPRmt regulation. Furthermore, we will explore the current repertoire of biological functions that are associated with this essential stress-response pathway.


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 ...


Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson Aug 2017

Cross-Sectional Relations Of Whole-Blood Mirna Expression Levels And Hand Grip Strength In A Community Sample, Joanne M. Murabito, Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson

UMass Metabolic Network Publications

MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community-based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed-effects regression modeling of grip strength (kg) versus continuous miRNA 'Cq' values and versus binary miRNA expression was performed. We conducted an integrative miRNA-mRNA coexpression analysis and examined the enrichment of biologic pathways ...


Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin Aug 2017

Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin

UMass Metabolic Network Publications

OBJECTIVE: Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and ...


Prospective Relation Of Circulating Adipokines To Incident Metabolic Syndrome: The Framingham Heart Study, Justin P. Zachariah, Rene Quiroz, Kerrie P. Nelson, Zhaoyang Teng, John F. Keaney Jr., Lisa M. Sullivan, Ramachandran S. Vasan Jul 2017

Prospective Relation Of Circulating Adipokines To Incident Metabolic Syndrome: The Framingham Heart Study, Justin P. Zachariah, Rene Quiroz, Kerrie P. Nelson, Zhaoyang Teng, John F. Keaney Jr., Lisa M. Sullivan, Ramachandran S. Vasan

UMass Metabolic Network Publications

BACKGROUND: Adipokines are elaborated by adipose tissue and are associated with glycemic, lipid, and vascular traits. We hypothesized that in a cross-sectional analysis circulating adipokines are altered among subsets of obesity stratified by presence versus absence of metabolic syndrome (MetS) and prospectively predict the incidence of MetS.

METHODS AND RESULTS: Participants in the community-based Framingham Third Generation Cohort who attended examination cycle 1 were included in the study (2002-2005; N=3777, mean age, 40 years; 59% women). Circulating adiponectin, leptin, leptin receptor, fetuin-A, fatty acid-binding protein 4, and retinol binding protein 4 were assayed and related to incident MetS in ...


Joint Analysis Of Left Ventricular Expression And Circulating Plasma Levels Of Omentin After Myocardial Ischemia, Louis A. Saddic, Sarah M. Nicoloro, Olga T. Gupta, Michael P. Czech, Joshua Gorham, Stanton K. Shernan, Christine E. Seidman, Jon G. Seidman, Sary F. Aranki, Simon C. Body, Timothy P. Fitzgibbons, Jochen D. Muehlschlegel Jul 2017

Joint Analysis Of Left Ventricular Expression And Circulating Plasma Levels Of Omentin After Myocardial Ischemia, Louis A. Saddic, Sarah M. Nicoloro, Olga T. Gupta, Michael P. Czech, Joshua Gorham, Stanton K. Shernan, Christine E. Seidman, Jon G. Seidman, Sary F. Aranki, Simon C. Body, Timothy P. Fitzgibbons, Jochen D. Muehlschlegel

UMass Metabolic Network Publications

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia.

METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled ...


Hypothalamic Ampk-Er Stress-Jnk1 Axis Mediates The Central Actions Of Thyroid Hormones On Energy Balance, Noelia Martinez-Sanchez, Roger J. Davis, Miguel Lopez Jul 2017

Hypothalamic Ampk-Er Stress-Jnk1 Axis Mediates The Central Actions Of Thyroid Hormones On Energy Balance, Noelia Martinez-Sanchez, Roger J. Davis, Miguel Lopez

UMass Metabolic Network Publications

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid ...


Map4k4 Impairs Energy Metabolism In Endothelial Cells And Promotes Insulin Resistance In Obesity, Rachel J. Roth Flach, Marina T. Distefano, Laura V. Danai, Ozlem Senol-Cosar, Joseph C. Yawe, Mark Kelly, Lorena Garcia Menendez, Michael P. Czech Jun 2017

Map4k4 Impairs Energy Metabolism In Endothelial Cells And Promotes Insulin Resistance In Obesity, Rachel J. Roth Flach, Marina T. Distefano, Laura V. Danai, Ozlem Senol-Cosar, Joseph C. Yawe, Mark Kelly, Lorena Garcia Menendez, Michael P. Czech

UMass Metabolic Network Publications

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) Mitogen activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte ...


Adipocyte Lipid Synthesis Coupled To Neuronal Control Of Thermogenic Programming, Adilson L. Guilherme, David J. Pedersen, Elizabeth Henchey, Felipe S. Henriques, Laura V. Danai, Yuefei Shen, Batuhan Yenilmez, Dae Young Jung, Jason K. Kim, Irfan J. Lodhi, Clay F. Semenkovich, Michael P. Czech May 2017

Adipocyte Lipid Synthesis Coupled To Neuronal Control Of Thermogenic Programming, Adilson L. Guilherme, David J. Pedersen, Elizabeth Henchey, Felipe S. Henriques, Laura V. Danai, Yuefei Shen, Batuhan Yenilmez, Dae Young Jung, Jason K. Kim, Irfan J. Lodhi, Clay F. Semenkovich, Michael P. Czech

UMass Metabolic Network Publications

BACKGROUND: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood.

METHODS and RESULTS: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT). Induced deletion of FASN in white and brown adipocytes of mature mice (iAdFASNKO mice) enhanced glucose tolerance, UCP1 expression, and cAMP signaling in iWAT ...


Jak/Stat Pathway Inhibition Overcomes Il7-Induced Glucocorticoid Resistance In A Subset Of Human T-Cell Acute Lymphoblastic Leukemias, C. Delgado-Martin, L. K. Meyer, B. J. Huang, M. S. Zinter, J. V. Nguyen, G. A. Smith, J. Taunton, S. S. Winter, Justine R. Roderick, Michelle A. Kelliher, T. M. Horton, B. L. Wood, D. T. Teachey, M. L. Hermiston May 2017

Jak/Stat Pathway Inhibition Overcomes Il7-Induced Glucocorticoid Resistance In A Subset Of Human T-Cell Acute Lymphoblastic Leukemias, C. Delgado-Martin, L. K. Meyer, B. J. Huang, M. S. Zinter, J. V. Nguyen, G. A. Smith, J. Taunton, S. S. Winter, Justine R. Roderick, Michelle A. Kelliher, T. M. Horton, B. L. Wood, D. T. Teachey, M. L. Hermiston

UMass Metabolic Network Publications

While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling ...


Mitochondrial Retrograde Signaling Connects Respiratory Capacity To Thermogenic Gene Expression, Minwoo Nam, Thomas E. Akie, Masato Sanosaka, Siobhan M. Craige, Shashi Kant, John F. Keaney Jr., Marcus P. Cooper May 2017

Mitochondrial Retrograde Signaling Connects Respiratory Capacity To Thermogenic Gene Expression, Minwoo Nam, Thomas E. Akie, Masato Sanosaka, Siobhan M. Craige, Shashi Kant, John F. Keaney Jr., Marcus P. Cooper

UMass Metabolic Network Publications

Mitochondrial respiration plays a crucial role in determining the metabolic state of brown adipose tissue (BAT), due to its direct roles in thermogenesis, as well as through additional mechanisms. Here, we show that respiration-dependent retrograde signaling from mitochondria to nucleus contributes to genetic and metabolic reprogramming of BAT. In mouse BAT, ablation of LRPPRC (LRP130), a potent regulator of mitochondrial transcription and respiratory capacity, triggers down-regulation of thermogenic genes, promoting a storage phenotype in BAT. This retrograde regulation functions by inhibiting the recruitment of PPARgamma to the regulatory elements of thermogenic genes. Reducing cytosolic Ca2+ reverses the attenuation of thermogenic ...


Differential Involvement Of The Microtubule Cytoskeleton In Insulin Receptor Substrate 1 (Irs-1) And Irs-2 Signaling To Akt Determines The Response To Microtubule Disruption In Breast Carcinoma Cells, Jose Mercado-Matos, Jennifer L. Clark, Andrew J. Piper, Jenny Janusis, Leslie M. Shaw May 2017

Differential Involvement Of The Microtubule Cytoskeleton In Insulin Receptor Substrate 1 (Irs-1) And Irs-2 Signaling To Akt Determines The Response To Microtubule Disruption In Breast Carcinoma Cells, Jose Mercado-Matos, Jennifer L. Clark, Andrew J. Piper, Jenny Janusis, Leslie M. Shaw

UMass Metabolic Network Publications

The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to ...


Runx1 And Breast Cancer, Jose Mercado-Matos, Asia N. Matthew-Onabanjo, Leslie M. Shaw Apr 2017

Runx1 And Breast Cancer, Jose Mercado-Matos, Asia N. Matthew-Onabanjo, Leslie M. Shaw

UMass Metabolic Network Publications

News on: Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition, by Hong et al. Oncotarget. 2017; 8:17610-27. doi: 10.18632/oncotarget.15381.


Mammalian Swi/Snf Enzymes And The Epigenetics Of Tumor Cell Metabolic Reprogramming, Jeffrey A. Nickerson, Qiong Wu, Anthony N. Imbalzano Apr 2017

Mammalian Swi/Snf Enzymes And The Epigenetics Of Tumor Cell Metabolic Reprogramming, Jeffrey A. Nickerson, Qiong Wu, Anthony N. Imbalzano

UMass Metabolic Network Publications

Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as ...


The Connection Between Brg1, Ctcf And Topoisomerases At Tad Boundaries, Ahmet Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein, Anthony N. Imbalzano Mar 2017

The Connection Between Brg1, Ctcf And Topoisomerases At Tad Boundaries, Ahmet Rasim Barutcu, Jane B. Lian, Janet L. Stein, Gary S. Stein, Anthony N. Imbalzano

UMass Metabolic Network Publications

The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries. In this review, we elaborate on our findings ...