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Journal of Clinical Investigation

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https://www.readbyqxmd.com/read/29035283/mtorc1-stimulates-phosphatidylcholine-synthesis-to-promote-triglyceride-secretion
#1
William J Quinn, Min Wan, Swapnil V Shewale, Rebecca Gelfer, Daniel J Rader, Morris J Birnbaum, Paul M Titchenell
Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035282/endothelial-transplantation-rejuvenates-aged-hematopoietic-stem-cell-function
#2
Michael G Poulos, Pradeep Ramalingam, Michael C Gutkin, Pierre Llanos, Katherine Gilleran, Sina Y Rabbany, Jason M Butler
Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035281/young-endothelial-cells-revive-aging-blood
#3
Vivian Y Chang, Christina M Termini, John P Chute
The hematopoietic system declines with age, resulting in decreased hematopoietic stem cell (HSC) self-renewal capacity, myeloid skewing, and immune cell depletion. Aging of the hematopoietic system is associated with an increased incidence of myeloid malignancies and a decline in adaptive immunity. Therefore, strategies to rejuvenate the hematopoietic system have important clinical implications. In this issue of the JCI, Poulos and colleagues demonstrate that infusions of bone marrow (BM) endothelial cells (ECs) from young mice promoted HSC self-renewal and restored immune cell content in aged mice...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035280/adipocyte-cannabinoid-receptor-cb1-regulates-energy-homeostasis-and-alternatively-activated-macrophages
#4
Inigo Ruiz de Azua, Giacomo Mancini, Raj Kamal Srivastava, Alejandro Aparisi Rey, Pierre Cardinal, Laura Tedesco, Cristina Maria Zingaretti, Antonia Sassmann, Carmelo Quarta, Claudia Schwitter, Andrea Conrad, Nina Wettschureck, V Kiran Vemuri, Alexandros Makriyannis, Jens Hartwig, Maria Mendez-Lago, Laura Bindila, Krisztina Monory, Antonio Giordano, Saverio Cinti, Giovanni Marsicano, Stefan Offermanns, Enzo Nisoli, Uberto Pagotto, Daniela Cota, Beat Lutz
Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035279/cannabis-in-fat-high-hopes-to-treat-obesity
#5
Melody N Hawkins, Tamas L Horvath
Cannabinoid receptor type-1 (CB1s) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. In this issue of the JCI, Ruiz de Azua and colleagues provide important insights into the regulation of adipocyte physiology by CB1. Mice with adipocyte-specific deletion of the CB1-encoding gene had an overall improved metabolic profile in addition to reduced body weight and total adiposity. These changes were associated with an increase in sympathetic tone of the adipose tissue and expansion of activated macrophages, both of which occurred prior to changes in body weight, lending support to a causal relationship between loss of CB1 in adipocytes and systemic metabolic changes...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035278/hdac3-regulates-lymphovenous-and-lymphatic-valve-formation
#6
Harish P Janardhan, Zachary J Milstone, Masahiro Shin, Nathan D Lawson, John F Keaney, Chinmay M Trivedi
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...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29035277/mnk1-2-inhibition-limits-oncogenicity-and-metastasis-of-kit-mutant-melanoma
#7
Yao Zhan, Jun Guo, William Yang, Christophe Goncalves, Tomasz Rzymski, Agnieszka Dreas, Eliza Żyłkiewicz, Maciej Mikulski, Krzysztof Brzózka, Aniela Golas, Yan Kong, Meng Ma, Fan Huang, Bonnie Huor, Qianyu Guo, Sabrina Daniela da Silva, Jose Torres, Yutian Cai, Ivan Topisirovic, Jie Su, Krikor Bijian, Moulay A Alaoui-Jamali, Sidong Huang, Fabrice Journe, Ghanem E Ghanem, Wilson H Miller, Sonia V Del Rincón
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic...
October 16, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28990936/olfactory-receptor-544-reduces-adiposity-by-steering-fuel-preference-toward-fats
#8
Chunyan Wu, Su Hyeon Hwang, Yaoyao Jia, Joobong Choi, Yeon-Ji Kim, Dahee Choi, Duleepa Pathiraja, In-Geol Choi, Seung-Hoi Koo, Sung-Joon Lee
Olfactory receptors (ORs) are present in tissues outside the olfactory system; however, the function of these receptors remains relatively unknown. Here, we determined that olfactory receptor 544 (Olfr544) is highly expressed in the liver and adipose tissue of mice and regulates cellular energy metabolism and obesity. Azelaic acid (AzA), an Olfr544 ligand, specifically induced PKA-dependent lipolysis in adipocytes and promoted fatty acid oxidation (FAO) and ketogenesis in liver, thus shifting the fuel preference to fats...
October 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28990935/caspase-11-mediated-endothelial-pyroptosis-underlies-endotoxemia-induced-lung-injury
#9
Kwong Tai Cheng, Shiqin Xiong, Zhiming Ye, Zhigang Hong, Anke Di, Kit Man Tsang, Xiaopei Gao, Shejuan An, Manish Mittal, Stephen M Vogel, Edward A Miao, Jalees Rehman, Asrar B Malik
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo...
October 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28990934/mast-cell-hyperactivity-underpins-the-development-of-oxygen-induced-retinopathy
#10
Kenshiro Matsuda, Noriko Okamoto, Masatoshi Kondo, Peter D Arkwright, Kaoru Karasawa, Saori Ishizaka, Shinichi Yokota, Akira Matsuda, Kyungsook Jung, Kumiko Oida, Yosuke Amagai, Hyosun Jang, Eiichiro Noda, Ryota Kakinuma, Koujirou Yasui, Uiko Kaku, Yasuo Mori, Nobuyuki Onai, Toshiaki Ohteki, Akane Tanaka, Hiroshi Matsuda
Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT)...
October 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28990933/circulating-osteocrin-stimulates-bone-growth-by-limiting-c-type-natriuretic-peptide-clearance
#11
Yugo Kanai, Akihiro Yasoda, Keita P Mori, Haruko Watanabe-Takano, Chiaki Nagai-Okatani, Yui Yamashita, Keisho Hirota, Yohei Ueda, Ichiro Yamauchi, Eri Kondo, Shigeki Yamanaka, Yoriko Sakane, Kazumasa Nakao, Toshihito Fujii, Hideki Yokoi, Naoto Minamino, Masashi Mukoyama, Naoki Mochizuki, Nobuya Inagaki
Although peptides are safe and useful as therapeutics, they are often easily degraded or metabolized. Dampening the clearance system for peptide ligands is a promising strategy for increasing the efficacy of peptide therapies. Natriuretic peptide receptor B (NPR-B) and its naturally occurring ligand, C-type natriuretic peptide (CNP), are potent stimulators of endochondral bone growth, and activating the CNP/NPR-B system is expected to be a powerful strategy for treating impaired skeletal growth. CNP is cleared by natriuretic peptide clearance receptor (NPR-C); therefore, we investigated the effect of reducing the rate of CNP clearance on skeletal growth by limiting the interaction between CNP and NPR-C...
October 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28990932/uromodulin-p-cys147trp-mutation-drives-kidney-disease-by-activating-er-stress-and-apoptosis
#12
Bryce G Johnson, Lan T Dang, Graham Marsh, Allie M Roach, Zebulon G Levine, Anthony Monti, Deepak Reyon, Lionel Feigenbaum, Jeremy S Duffield
Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result in a misfolded form of UMOD protein, which is normally secreted by nephrons. In UAKD patients, mutant UMOD is poorly secreted and accumulates in the ER of distal kidney epithelium, but its role in disease progression is largely unknown. Here, we modeled UMOD accumulation in mice by expressing the murine equivalent of the human UMOD p.Cys148Trp point mutation (UmodC147W/+ mice). Like affected humans, these UmodC147W/+ mice developed spontaneous and progressive kidney disease with organ failure over 24 weeks...
October 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28972541/camkii%C3%AE-suppresses-an-efferocytosis-pathway-in-macrophages-and-promotes-atherosclerotic-plaque-necrosis
#13
Amanda C Doran, Lale Ozcan, Bishuang Cai, Ze Zheng, Gabrielle Fredman, Christina C Rymond, Bernhard Dorweiler, Judith C Sluimer, Joanne Hsieh, George Kuriakose, Alan R Tall, Ira Tabas
Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages plays a major role in the development of necrotic, thin-capped plaques...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28972540/proprotein-convertase-furin-regulates-osteocalcin-and-bone-endocrine-function
#14
Omar El-Rifai, Jacqueline Chow, Julie Lacombe, Catherine Julien, Denis Faubert, Delia Susan-Resiga, Rachid Essalmani, John Wm Creemers, Nabil G Seidah, Mathieu Ferron
Osteocalcin (OCN) is an osteoblast-derived hormone that increases energy expenditure, insulin sensitivity, insulin secretion, and glucose tolerance. The cDNA sequence of OCN predicts that, like many other peptide hormones, OCN is first synthesized as a prohormone (pro-OCN). The importance of pro-OCN maturation in regulating OCN and the identity of the endopeptidase responsible for pro-OCN cleavage in osteoblasts are still unknown. Here, we show that the proprotein convertase furin is responsible for pro-OCN maturation in vitro and in vivo...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28972539/cd56bright-nk-cells-exhibit-potent-antitumor-responses-following-il-15-priming
#15
Julia A Wagner, Maximillian Rosario, Rizwan Romee, Melissa M Berrien-Elliott, Stephanie E Schneider, Jeffrey W Leong, Ryan P Sullivan, Brea A Jewell, Michelle Becker-Hapak, Timothy Schappe, Sara Abdel-Latif, Aaron R Ireland, Devika Jaishankar, Justin A King, Ravi Vij, Dennis Clement, Jodie Goodridge, Karl-Johan Malmberg, Hing C Wong, Todd A Fehniger
NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28972538/mutations-in-signal-recognition-particle-srp54-cause-syndromic-neutropenia-with-shwachman-diamond-like-features
#16
Raphael Carapito, Martina Konantz, Catherine Paillard, Zhichao Miao, Angélique Pichot, Magalie S Leduc, Yaping Yang, Katie L Bergstrom, Donald H Mahoney, Deborah L Shardy, Ghada Alsaleh, Lydie Naegely, Aline Kolmer, Nicodème Paul, Antoine Hanauer, Véronique Rolli, Joëlle S Müller, Elisa Alghisi, Loïc Sauteur, Cécile Macquin, Aurore Morlon, Consuelo Sebastia Sancho, Patrizia Amati-Bonneau, Vincent Procaccio, Anne-Laure Mosca-Boidron, Nathalie Marle, Naël Osmani, Olivier Lefebvre, Jacky G Goetz, Sule Unal, Nurten A Akarsu, Mirjana Radosavljevic, Marie-Pierre Chenard, Fanny Rialland, Audrey Grain, Marie-Christine Béné, Marion Eveillard, Marie Vincent, Julien Guy, Laurence Faivre, Christel Thauvin-Robinet, Julien Thevenon, Kasiani Myers, Mark D Fleming, Akiko Shimamura, Elodie Bottollier-Lemallaz, Eric Westhof, Claudia Lengerke, Bertrand Isidor, Seiamak Bahram
Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa)...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28972537/divergent-effects-of-glucose-and-fructose-on-hepatic-lipogenesis-and-insulin-signaling
#17
Samir Softic, Manoj K Gupta, Guo-Xiao Wang, Shiho Fujisaka, Brian T O'Neill, Tata Nageswara Rao, Jennifer Willoughby, Carole Harbison, Kevin Fitzgerald, Olga Ilkayeva, Christopher B Newgard, David E Cohen, C Ronald Kahn
Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake...
October 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28945203/mtorc1-loss-impairs-epidermal-adhesion-via-tgf-%C3%AE-rho-kinase-activation
#18
Kaushal Asrani, Akshay Sood, Alba Torres, Dan Georgess, Pornima Phatak, Harsimar Kaur, Amber Dubin, C Conover Talbot, Loubna Elhelu, Andrew J Ewald, Bo Xiao, Paul Worley, Tamara L Lotan
Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation...
September 25, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28945202/commensal-propionibacterium-strain-uf1-mitigates-intestinal-inflammation-via-th17-cell-regulation
#19
Natacha Colliou, Yong Ge, Bikash Sahay, Minghao Gong, Mojgan Zadeh, Jennifer L Owen, Josef Neu, William G Farmerie, Francis Alonzo, Ken Liu, Dean P Jones, Shuzhao Li, Mansour Mohamadzadeh
Consumption of human breast milk (HBM) attenuates the incidence of necrotizing enterocolitis (NEC), which remains a leading and intractable cause of mortality in preterm infants. Here, we report that this diminution correlates with alterations in the gut microbiota, particularly enrichment of Propionibacterium species. Transfaunation of microbiota from HBM-fed preterm infants or a newly identified and cultured Propionibacterium strain, P. UF1, to germfree mice conferred protection against pathogen infection and correlated with profound increases in intestinal Th17 cells...
September 25, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28945201/enterobacteria-secrete-an-inhibitor-of-pseudomonas-virulence-during-clinical-bacteriuria
#20
Shannon I Ohlemacher, Daryl E Giblin, D André d'Avignon, Ann E Stapleton, Barbara W Trautner, Jeffrey P Henderson
Escherichia coli and other Enterobacteriaceae are among the most common pathogens of the human urinary tract. Among the genetic gains of function associated with urinary E. coli isolates is the Yersinia high pathogenicity island (HPI), which directs the biosynthesis of yersiniabactin (Ybt), a virulence-associated metallophore. Using a metabolomics approach, we found that E. coli and other Enterobacteriaceae expressing the Yersinia HPI also secrete escherichelin, a second metallophore whose chemical structure matches a known synthetic inhibitor of the virulence-associated pyochelin siderophore system in Pseudomonas aeruginosa...
September 25, 2017: Journal of Clinical Investigation
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