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https://www.readbyqxmd.com/read/29789271/molecular-elements-in-fgf19-and-fgf21-defining-klb-fgfr-activity-and-specificity
#1
Archita Agrawal, Sebastian Parlee, Diego Perez-Tilve, Pengyun Li, Jia Pan, Piotr A Mroz, Ann Maria Kruse Hansen, Birgitte Andersen, Brian Finan, Alexei Kharitonenkov, Richard D DiMarchi
OBJECTIVE: To signal, FGF19 and FGF21 require co-receptor βKlotho (KLB) to act in concert with FGF receptors, and yet there is appreciable variance in the C-terminal sequences of these two novel metabolic hormones where binding is believed to be primary. We seek to determine the functional consequences for these amino acid differences and determine whether such information can be used to design high potency antagonists and agonists. METHODS: We employed a functional in vitro assay to identify C-terminal protein fragments capable of fully blocking KLB-mediated FGF19 and 21 receptor signaling...
May 11, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29734515/decreased-placental-and-muscular-expression-of-the-fibroblast-growth-factor-19-in-gestational-diabetes-mellitus
#2
Dongyu Wang, Shuqia Xu, Wenjing Ding, Caixia Zhu, Songqing Deng, Xiwen Qiu, Zilian Wang
AIMS: Fibroblast growth factor (FGF) 19 has been shown to improve glycaemic homeostasis and lipid metabolism in animal models. In humans, decreased FGF19 level has been described in diabetes. This study aimed to investigate the expression of FGF19 in gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Samples for measurement were obtained from 20 GDM women and 25 healthy controls. The mRNA and protein expression levels of FGF19, FGF21 and co-receptor β-klotho (KLB) in placenta, rectus muscle and subcutaneous fat tissues were quantified by real-time quantitative polymerase chain reaction, western-blot and immunohistochemistry, respectively...
May 7, 2018: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/29717197/effects-of-ngm282-an-fgf19-variant-on-colonic-transit-and-bowel-function-in-functional-constipation-a-randomized-phase-2-trial
#3
Ibironke Oduyebo, Michael Camilleri, Alfred D Nelson, Disha Khemani, Sara Linker Nord, Irene Busciglio, Duane Burton, Deborah Rhoten, Michael Ryks, Paula Carlson, Leslie Donato, Alan Lueke, Kathline Kim, Stephen J Rossi, Alan R Zinsmeister
OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3...
May 2, 2018: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/29661866/reciprocal-effects-of-antiretroviral-drugs-used-to-treat-hiv-infection-on-the-fibroblast-growth-factor-21-%C3%AE-klotho-system
#4
Ricardo Moure, Pere Domingo, Joan Villarroya, Laura Gasa, José M Gallego-Escuredo, Tania Quesada-López, Samantha Morón-Ros, Alberto F Maroto, Gracia M Mateo, Joan C Domingo, Francesc Villarroya, Marta Giralt
Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor-21 (FGF21). In contrast, expression of the FGF21-obligatory co-receptor β-Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type-2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells...
April 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29660397/a-pharmacology-guided-approach-for-setting-limits-on-product-related-impurities-for-bispecific-antibody-manufacturing
#5
Sharmila Rajan, Junichiro Sonoda, Timothy Tully, Ambrose J Williams, Feng Yang, Frank Macchi, Terry Hudson, Mark Z Chen, Shannon Liu, Nicole Valle, Kyra Cowan, Thomas Gelzleichter
INTRODUCTION: bFKB1 is a humanized bispecific IgG1 antibody, created by conjoining an anti-Fibroblast Growth Factor Receptor 1 (FGFR1) half-antibody to an anti-Klothoβ (KLB) half-antibody, using the knobs-into-holes strategy. bFKB1 acts as a highly selective agonist for the FGFR1/KLB receptor complex and is intended to ameliorate obesity-associated metabolic defects by mimicking the activity of the hormone FGF21. An important aspect of the biologics product manufacturing process is to establish meaningful product specifications regarding the tolerable levels of impurities that copurify with the drug product...
April 13, 2018: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/29627377/fgf21-a-liver-hormone-that-inhibits-alcohol-intake-in-mice-increases-in-human-circulation-after-acute-alcohol-ingestion-and-sustained-binge-drinking-at-oktoberfest
#6
Susanna Søberg, Emilie S Andersen, Niels B Dalgaard, Ida Jarlhelt, Nina L Hansen, Nina Hoffmann, Tina Vilsbøll, Anne Chenchar, Michal Jensen, Trisha J Grevengoed, Sam A J Trammell, Filip K Knop, Matthew P Gillum
OBJECTIVE: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers...
March 27, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29601195/biosynthesis-of-translation-inhibitor-klebsazolicin-proceeds-through-heterocyclisation-and-n-terminal-amidine-formation-catalysed-by-a-single-ycao-enzyme
#7
Dmitrii Y Travin, Mikhail Metelev, Marina Serebryakova, Ekaterina Komarova, Ilya A Osterman, Dmitry Ghilarov, Konstantin Severinov
Klebsazolicin (KLB) is a recently discovered Klebsiella pneumoniae peptide antibiotic targeting the exit tunnel of bacterial ribosome. KLB contains an N-terminal amidine ring and four azole heterocycles installed into a ribosomally-synthesized precursor by dedicated maturation machinery. Using in vitro system for KLB production, we show that the YcaO-domain KlpD maturation enzyme is a bifunctional cyclodehydratase required for the formation of both the core heterocycles and the N-terminal amidine ring. We further demonstrate that the amidine ring is formed concomitantly with proteolytic cleavage of azole-containing pro-KLB by a cellular protease TldD/E...
March 30, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29593555/ileal-transposition-surgery-decreases-fat-mass-and-improves-glucose-metabolism-in-diabetic-gk-rats-possible-involvement-of-fgf21
#8
Kemin Yan, Weijie Chen, Huijuan Zhu, Guole Lin, Hui Pan, Naishi Li, Linjie Wang, Hongbo Yang, Meijuan Liu, Fengying Gong
Objective: Ileal transposition (IT) surgery has been reported to improve glucose and lipid metabolism, and fibroblast growth factor 21 (FGF21) is a powerful metabolic regulator. In the present study, we aimed to investigate the effects of IT surgery on metabolism and its possible relationship with the FGF21 signaling pathway in diabetic Goto-Kakizaki (GK) rats. Methods: Ten-week-old male GK rats were subjected to IT surgery with translocation of a 10 cm ileal segment to the proximal jejunum (IT group) or sham surgery without the ileum transposition (Sham-IT group)...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29432567/bile-acid-sequestration-by-cholestyramine-mitigates-fgfr4-inhibition-induced-alt-elevation
#9
Heiko S Schadt, Armin Wolf, Joerg Andreas Mahl, Kuno Wuersch, Philippe Couttet, Marianne Schwald, Audrey Fischer, Mathilde Lienard, Corinne Emotte, Chi-Hse Teng, Elizabeth Skuba, Terrilyn A Richardson, Luigi Manenti, Andreas Weiss, Diana Graus Porta, Robin A Fairhurst, Gerd A Kullak-Ublick, Salah-Dine Chibout, Francois Pognan, William Kluwe, Jacqueline Kinyamu-Akunda
The FGF19- fibroblast growth factor receptor (FGFR4)-βKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies...
May 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29344186/downregulation-of-klotho-%C3%AE-is-associated-with-invasive-ductal-carcinoma-progression
#10
Ping Li, Meng Zhao, Xiaoli Qi, Xuegong Zhu, Jie Dai
Klotho β (KLB) is a single-pass transmembrane protein measuring 1,043 amino acids in length that shares 41.2% homology with klotho α (KLA). KLB is a co-receptor and key regulator of the fibroblast growth factor receptor 4 (FGFR4) pathway. KLB interacts with FGFR4 to induce apoptosis and inhibit the proliferation of hepatoma cells, and KLA has been demonstrated to be a tumor suppressor in human breast cancer; however, little is known regarding the role of KLB in breast cancer. In the present study, through an immunohistochemical analysis of invasive ductal carcinoma tissue arrays, low KLB expression was identified in invasive ductal carcinoma samples compared with paired adjacent non-tumorous breast tissues (82 cases)...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29098321/sugar-sweetened-beverage-intake-associations-with-fasting-glucose-and-insulin-concentrations-are-not-modified-by-selected-genetic-variants-in-a-chrebp-fgf21-pathway-a-meta-analysis
#11
Nicola M McKeown, Hassan S Dashti, Jiantao Ma, Danielle E Haslam, Jessica C Kiefte-de Jong, Caren E Smith, Toshiko Tanaka, Mariaelisa Graff, Rozenn N Lemaitre, Denis Rybin, Emily Sonestedt, Alexis C Frazier-Wood, Dennis O Mook-Kanamori, Yanping Li, Carol A Wang, Elisabeth T M Leermakers, Vera Mikkilä, Kristin L Young, Kenneth J Mukamal, L Adrienne Cupples, Christina-Alexandra Schulz, Tzu-An Chen, Ruifang Li-Gao, Tao Huang, Wendy H Oddy, Olli Raitakari, Kenneth Rice, James B Meigs, Ulrika Ericson, Lyn M Steffen, Frits R Rosendaal, Albert Hofman, Mika Kähönen, Bruce M Psaty, Louise Brunkwall, Andre G Uitterlinden, Jorma Viikari, David S Siscovick, Ilkka Seppälä, Kari E North, Dariush Mozaffarian, Josée Dupuis, Marju Orho-Melander, Stephen S Rich, Renée de Mutsert, Lu Qi, Craig E Pennell, Oscar H Franco, Terho Lehtimäki, Mark A Herman
AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits...
February 2018: Diabetologia
https://www.readbyqxmd.com/read/28937693/genome-wide-association-study-of-alcohol-consumption-and-genetic-overlap-with-other-health-related-traits-in-uk-biobank-n-112-117
#12
T-K Clarke, M J Adams, G Davies, D M Howard, L S Hall, S Padmanabhan, A D Murray, B H Smith, A Campbell, C Hayward, D J Porteous, I J Deary, A M McIntosh
Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals...
October 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28886439/chronic-high-sucrose-diet-increases-fibroblast-growth-factor-21-production-and-energy-expenditure-in-mice
#13
Ryuya Maekawa, Yusuke Seino, Hidetada Ogata, Masatoshi Murase, Atsushi Iida, Kaori Hosokawa, Erina Joo, Norio Harada, Shin Tsunekawa, Yoji Hamada, Yutaka Oiso, Nobuya Inagaki, Yoshitaka Hayashi, Hiroshi Arima
Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks...
November 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/28846667/klebsazolicin-inhibits-70s-ribosome-by-obstructing-the-peptide-exit-tunnel
#14
Mikhail Metelev, Ilya A Osterman, Dmitry Ghilarov, Nelli F Khabibullina, Alexander Yakimov, Konstantin Shabalin, Irina Utkina, Dmitry Y Travin, Ekaterina S Komarova, Marina Serebryakova, Tatyana Artamonova, Mikhail Khodorkovskii, Andrey L Konevega, Petr V Sergiev, Konstantin Severinov, Yury S Polikanov
Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity...
October 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28754744/-klb-encoding-%C3%AE-klotho-is-mutated-in-patients-with-congenital-hypogonadotropic-hypogonadism
#15
Cheng Xu, Andrea Messina, Emmanuel Somm, Hichem Miraoui, Tarja Kinnunen, James Acierno, Nicolas J Niederländer, Justine Bouilly, Andrew A Dwyer, Yisrael Sidis, Daniele Cassatella, Gerasimos P Sykiotis, Richard Quinton, Christian De Geyter, Mirjam Dirlewanger, Valérie Schwitzgebel, Trevor R Cole, Andrew A Toogood, Jeremy Mw Kirk, Lacey Plummer, Urs Albrecht, William F Crowley, Moosa Mohammadi, Manuel Tena-Sempere, Vincent Prevot, Nelly Pitteloud
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 ( FGFR1 ) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co-receptor for FGF21...
October 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28721439/effects-of-insulin-and-exercise-training-on-fgf21-its-receptors-and-target-genes-in-obesity-and-type-2-diabetes
#16
Rikke Kruse, Sara G Vienberg, Birgitte F Vind, Birgitte Andersen, Kurt Højlund
AIMS/HYPOTHESIS: Pharmacological doses of FGF21 improve glucose tolerance, lipid metabolism and energy expenditure in rodents. Induced expression and secretion of FGF21 from muscle may increase browning of white adipose tissue (WAT) in a myokine-like manner. Recent studies have reported that insulin and exercise increase FGF21 in plasma. Obesity and type 2 diabetes are potentially FGF21-resistant states, but to what extent FGF21 responses to insulin and exercise training are preserved, and whether FGF21, its receptors and target genes are altered, remains to be established...
October 2017: Diabetologia
https://www.readbyqxmd.com/read/28650457/fibroblast-growth-factor-19-regulates-skeletal-muscle-mass-and-ameliorates-muscle-wasting-in-mice
#17
Bérengère Benoit, Emmanuelle Meugnier, Martina Castelli, Stéphanie Chanon, Aurélie Vieille-Marchiset, Christine Durand, Nadia Bendridi, Sandra Pesenti, Pierre-Axel Monternier, Anne-Cécile Durieux, Damien Freyssenet, Jennifer Rieusset, Etienne Lefai, Hubert Vidal, Jérôme Ruzzin
The endocrine-derived hormone fibroblast growth factor (FGF) 19 has recently emerged as a potential target for treating metabolic disease. Given that skeletal muscle is a key metabolic organ, we explored the role of FGF19 in that tissue. Here we report a novel function of FGF19 in regulating skeletal muscle mass through enlargement of muscle fiber size, and in protecting muscle from atrophy. Treatment with FGF19 causes skeletal muscle hypertrophy in mice, while physiological and pharmacological doses of FGF19 substantially increase the size of human myotubes in vitro...
August 2017: Nature Medicine
https://www.readbyqxmd.com/read/28552744/reduction-in-serum-fibroblast-growth-factor-21-after-gastric-bypass-is-related-to-changes-in-hepatic-fat-content
#18
Karen Fjeldborg, Steen B Pedersen, Holger J Møller, Bjørn Richelsen
BACKGROUND: Fibroblast growth factor 21 (FGF21) is elevated in obesity. OBJECTIVES: We investigated the circulating level of FGF21 and the expression of FGF21, beta-klotho (KLB), and FGF receptor 1 (FGFR1) in adipose tissue in relation to weight, fat distribution, and Roux-en-Y gastric bypass (RYGB)-induced weight loss. SETTING: The Department of Endocrinology at Aarhus University Hospital. METHODS: Thirty-one obese patients were enrolled...
September 2017: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
https://www.readbyqxmd.com/read/28525362/fgf21-receptor-agonists-an-emerging-therapeutic-class-for-obesity-related-diseases
#19
REVIEW
Junichiro Sonoda, Mark Z Chen, Amos Baruch
Fibroblast growth factor 21 (FGF21) analogs and FGF21 receptor agonists (FGF21RAs) that mimic FGF21 ligand activity constitute the new "FGF21-class" of anti-obesity and anti-diabetic molecules that improve insulin sensitivity, ameliorate hepatosteatosis and promote weight loss. The metabolic actions of FGF21-class proteins in obese mice are attributed to stimulation of brown fat thermogenesis and increased secretion of adiponectin. The therapeutic utility of this class of molecules is being actively investigated in clinical trials for the treatment of type 2 diabetes and non-alcoholic steatohepatitis (NASH)...
May 19, 2017: Hormone Molecular Biology and Clinical Investigation
https://www.readbyqxmd.com/read/28485404/genetic-contributors-to-variation-in-alcohol-consumption-vary-by-race-ethnicity-in-a-large-multi-ethnic-genome-wide-association-study
#20
E Jorgenson, K K Thai, T J Hoffmann, L C Sakoda, M N Kvale, Y Banda, C Schaefer, N Risch, J Mertens, C Weisner, H Choquet
Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans...
September 2017: Molecular Psychiatry
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