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Mitchell A. Lazar

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https://www.readbyqxmd.com/read/28916805/an-hdac3-prox1-corepressor-module-acts-on-hnf4%C3%AE-to-control-hepatic-triglycerides
#1
Sean M Armour, Jarrett R Remsberg, Manashree Damle, Simone Sidoli, Wesley Y Ho, Zhenghui Li, Benjamin A Garcia, Mitchell A Lazar
The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α)...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28747429/the-hepatic-circadian-clock-fine-tunes-the-lipogenic-response-to-feeding-through-ror%C3%AE-%C3%AE
#2
Yuxiang Zhang, Romeo Papazyan, Manashree Damle, Bin Fang, Jennifer Jager, Dan Feng, Lindsey C Peed, Dongyin Guan, Zheng Sun, Mitchell A Lazar
Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check...
July 26, 2017: Genes & Development
https://www.readbyqxmd.com/read/28614293/histone-deacetylase-3-prepares-brown-adipose-tissue-for-acute-thermogenic-challenge
#3
Matthew J Emmett, Hee-Woong Lim, Jennifer Jager, Hannah J Richter, Marine Adlanmerini, Lindsey C Peed, Erika R Briggs, David J Steger, Tao Ma, Carrie A Sims, Joseph A Baur, Liming Pei, Kyoung-Jae Won, Patrick Seale, Zachary Gerhart-Hines, Mitchell A Lazar
Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure...
June 22, 2017: Nature
https://www.readbyqxmd.com/read/28416361/unraveling-the-regulation-of-hepatic-metabolism-by-insulin
#4
REVIEW
Paul M Titchenell, Mitchell A Lazar, Morris J Birnbaum
During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism...
July 2017: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/28368290/maturing-of-the-nuclear-receptor-family
#5
REVIEW
Mitchell A Lazar
Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the JCI includes a series of Review articles focused on specific NRs and their wide range of biological functions. Here I reflect on the past, present, and potential future highlights of research on the NR superfamily...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28240605/targeting-ppar%C3%AE-in-the-epigenome-rescues-genetic-metabolic-defects-in-mice
#6
Raymond E Soccio, Zhenghui Li, Eric R Chen, Yee Hoon Foong, Kiara K Benson, Joanna R Dispirito, Shannon E Mullican, Matthew J Emmett, Erika R Briggs, Lindsey C Peed, Richard K Dzeng, Carlos J Medina, Jennifer F Jolivert, Megan Kissig, Satyajit R Rajapurkar, Manashree Damle, Hee-Woong Lim, Kyoung-Jae Won, Patrick Seale, David J Steger, Mitchell A Lazar
Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28183511/proposed-standardized-neurological-endpoints-for-cardiovascular-clinical-trials-an-academic-research-consortium-initiative
#7
REVIEW
Alexandra J Lansky, Steven R Messé, Adam M Brickman, Michael Dwyer, H Bart van der Worp, Ronald M Lazar, Cody G Pietras, Kevin J Abrams, Eugene McFadden, Nils H Petersen, Jeffrey Browndyke, Bernard Prendergast, Vivian G Ng, Donald E Cutlip, Samir Kapadia, Mitchell W Krucoff, Axel Linke, Claudia Scala Moy, Joachim Schofer, Gerrit-Anne van Es, Renu Virmani, Jeffrey Popma, Michael K Parides, Susheel Kodali, Michel Bilello, Robert Zivadinov, Joseph Akar, Karen L Furie, Daryl Gress, Szilard Voros, Jeffrey Moses, David Greer, John K Forrest, David Holmes, Arie P Kappetein, Michael Mack, Andreas Baumbach
Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect...
February 14, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28123935/deletion-of-histone-deacetylase-3-in-adult-beta-cells-improves-glucose-tolerance-via-increased-insulin-secretion
#8
Jarrett R Remsberg, Benjamin N Ediger, Wesley Y Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A Stoffers, Mitchell A Lazar
OBJECTIVE: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. METHODS: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28059714/regeneration-of-fat-cells-from-myofibroblasts-during-wound-healing
#9
Maksim V Plikus, Christian F Guerrero-Juarez, Mayumi Ito, Yun Rose Li, Priya H Dedhia, Ying Zheng, Mengle Shao, Denise L Gay, Raul Ramos, Tsai-Ching Hsi, Ji Won Oh, Xiaojie Wang, Amanda Ramirez, Sara E Konopelski, Arijh Elzein, Anne Wang, Rarinthip June Supapannachart, Hye-Lim Lee, Chae Ho Lim, Arben Nace, Amy Guo, Elsa Treffeisen, Thomas Andl, Ricardo N Ramirez, Rabi Murad, Stefan Offermanns, Daniel Metzger, Pierre Chambon, Alan D Widgerow, Tai-Lan Tuan, Ali Mortazavi, Rana K Gupta, Bruce A Hamilton, Sarah E Millar, Patrick Seale, Warren S Pear, Mitchell A Lazar, George Cotsarelis
Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation...
February 17, 2017: Science
https://www.readbyqxmd.com/read/27991918/dissociation-of-muscle-insulin-sensitivity-from-exercise-endurance-in-mice-by-hdac3-depletion
#10
Sungguan Hong, Wenjun Zhou, Bin Fang, Wenyun Lu, Emanuele Loro, Manashree Damle, Guolian Ding, Jennifer Jager, Sisi Zhang, Yuxiang Zhang, Dan Feng, Qingwei Chu, Brian D Dill, Henrik Molina, Tejvir S Khurana, Joshua D Rabinowitz, Mitchell A Lazar, Zheng Sun
Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids...
February 2017: Nature Medicine
https://www.readbyqxmd.com/read/27922611/genetic-and-epigenomic-mechanisms-of-mammalian-circadian-transcription
#11
REVIEW
Romeo Papazyan, Yuxiang Zhang, Mitchell A Lazar
The mammalian molecular clock comprises a complex network of transcriptional programs that integrates environmental signals with physiological pathways in a tissue-specific manner. Emerging technologies are extending knowledge of basic clock features by uncovering their underlying molecular mechanisms, thus setting the stage for a 'systems' view of the molecular clock. Here we discuss how recent data from genome-wide genetic and epigenetic studies have informed the understanding of clock function. In addition to its importance in human physiology and disease, the clock mechanism provides an ideal model to assess general principles of dynamic transcription regulation in vivo...
December 6, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27885004/circadian-time-signatures-of-fitness-and-disease
#12
REVIEW
Joseph Bass, Mitchell A Lazar
Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time...
November 25, 2016: Science
https://www.readbyqxmd.com/read/27866836/physiological-suppression-of-lipotoxic-liver-damage%C3%A2-by-complementary-actions-of-hdac3-and%C3%A2-scap-srebp
#13
Romeo Papazyan, Zheng Sun, Yong Hoon Kim, Paul M Titchenell, David A Hill, Wenyun Lu, Manashree Damle, Min Wan, Yuxiang Zhang, Erika R Briggs, Joshua D Rabinowitz, Mitchell A Lazar
Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective...
December 13, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27689007/genetic-backgrounds-determine-brown-remodeling-of-white-fat-in-rodents
#14
Giulia Ferrannini, Maria Namwanje, Bin Fang, Manashree Damle, Dylan Li, Qiongming Liu, Mitchell A Lazar, Li Qiang
OBJECTIVE: Genetic background largely contributes to the complexity of metabolic responses and dysfunctions. Induction of brown adipose features in white fat, known as brown remodeling, has been appreciated as a promising strategy to offset the positive energy balance in obesity and further to improve metabolism. Here we address the effects of genetic background on this process. METHODS: We investigated browning remodeling in a depot-specific manner by comparing the response of C57BL/6J, 129/Sv and FVB/NJ mouse strains to cold...
October 2016: Molecular Metabolism
https://www.readbyqxmd.com/read/27445394/hnf6-and-rev-erb%C3%AE-integrate-hepatic-lipid-metabolism-by-overlapping-and-distinct-transcriptional-mechanisms
#15
Yuxiang Zhang, Bin Fang, Manashree Damle, Dongyin Guan, Zhenghui Li, Yong Hoon Kim, Maureen Gannon, Mitchell A Lazar
Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver...
July 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27434480/management-of-obstructive-sleep-apnea-in-children-a-practical-approach
#16
REVIEW
Kevin D Pereira, Cindy K Jon, Peter Szmuk, Rande H Lazar, Ron B Mitchell
The management of sleep disordered breathing (SDB) in children differs between institutions, and there is a need for an updated review of current practice. Literature was reviewed using the PubMed database from 1995 to 2015 by four tertiary care providers experienced in the management of children with SDB. Articles were selected for clinical applicability, strength of evidence, and practicality for practicing clinicians. Fifty-five articles were identified by tertiary care providers in pediatric anesthesiology, pediatric pulmonology, sleep medicine, and pediatric otolaryngology...
July 2016: Ear, Nose, & Throat Journal
https://www.readbyqxmd.com/read/27379724/american-neurophysiology-and-two-nineteenth-century-american-physiological-societies
#17
J Wayne Lazar
This article contrasts two American Physiological Societies, one founded near the beginning of the nineteenth century in 1837 and the other founded near its end in 1887. The contrast allows a perspective on how much budding neuroscience had developed during the nineteenth century in America. The contrast also emphasizes the complicated structure needed in both medicine and physiology to allow neurophysiology to flourish. The objectives of the American Physiological Society of 1887 were (and are) to promote physiological research and to codify physiology as a discipline...
July 5, 2016: Journal of the History of the Neurosciences
https://www.readbyqxmd.com/read/27333189/lactate-dehydrogenase-c-produces-s-2-hydroxyglutarate-in-mouse-testis
#18
Xin Teng, Matthew J Emmett, Mitchell A Lazar, Erwin Goldberg, Joshua D Rabinowitz
Metabolomics is a valuable tool for studying tissue- and organism-specific metabolism. In normal mouse testis, we found 70 μM S-2-hydroxyglutarate (2HG), more than 10-fold greater than in other tissues. S-2HG is a competitive inhibitor of α-ketoglutarate-dependent demethylation enzymes and can alter histone or DNA methylation. To identify the source of testis S-2HG, we fractionated testis extracts and identified the fractions that actively produced S-2HG. Through a combination of ion exchange and size exclusion chromatography, we enriched a single active protein, the lactate dehydrogenase isozyme LDHC, which is primarily expressed in testis...
September 16, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27326936/hdac3-interaction-with-p300-histone-acetyltransferase-regulates-the-oligodendrocyte-and-astrocyte-lineage-fate-switch
#19
Liguo Zhang, Xuelian He, Lei Liu, Minqing Jiang, Chuntao Zhao, Haibo Wang, Danyang He, Tao Zheng, Xianyao Zhou, Aishlin Hassan, Zhixing Ma, Mei Xin, Zheng Sun, Mitchell A Lazar, Steven A Goldman, Eric N Olson, Q Richard Lu
No abstract text is available yet for this article.
June 20, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27282397/histopathologic-review-of-pineal-parenchymal-tumors-identifies-novel-morphologic-subtypes-and-prognostic-factors-for-outcome
#20
David R Raleigh, David A Solomon, Shane A Lloyd, Ann Lazar, Michael A Garcia, Penny K Sneed, Jennifer L Clarke, Michael W McDermott, Mitchel S Berger, Tarik Tihan, Daphne A Haas-Kogan
BACKGROUND: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions. METHODS: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed...
January 2017: Neuro-oncology
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