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Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.
Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J
(2018) Eur Respir J 51:
MeSH Terms: Adult, Aged, Animals, Biomarkers, Cytokines, Female, Gene Expression, Humans, Hypertension, Pulmonary, Male, Middle Aged, Peptidyl-Dipeptidase A, Pilot Projects, Proof of Concept Study, Proto-Oncogene Proteins, Pulmonary Artery, Receptors, G-Protein-Coupled, Superoxide Dismutase, Swine, Vascular Resistance
Show Abstract · Added March 26, 2019
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Copyright ©ERS 2018.
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2 Members
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20 MeSH Terms
The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors.
Joedicke L, Mao J, Kuenze G, Reinhart C, Kalavacherla T, Jonker HRA, Richter C, Schwalbe H, Meiler J, Preu J, Michel H, Glaubitz C
(2018) Nat Chem Biol 14: 284-290
MeSH Terms: Animals, HEK293 Cells, Humans, Insecta, Kinins, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Docking Simulation, Mutation, Peptides, Protein Binding, Protein Domains, Protein Structure, Secondary, Receptor, Bradykinin B1, Receptor, Bradykinin B2, Receptors, G-Protein-Coupled, Sf9 Cells, Signal Transduction, Static Electricity
Show Abstract · Added March 17, 2018
G-protein-coupled receptors (GPCRs) are the most important signal transducers in higher eukaryotes. Despite considerable progress, the molecular basis of subtype-specific ligand selectivity, especially for peptide receptors, remains unknown. Here, by integrating DNP-enhanced solid-state NMR spectroscopy with advanced molecular modeling and docking, the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists has been resolved. The conserved middle segments of the bound peptides show distinct conformations that result in different presentations of their N and C termini toward their receptors. Analysis of the peptide-receptor interfaces reveals that the charged N-terminal residues of the peptides are mainly selected through electrostatic interactions, whereas the C-terminal segments are recognized via both conformations and interactions. The detailed molecular picture obtained by this approach opens a new gateway for exploring the complex conformational and chemical space of peptides and peptide analogs for designing GPCR subtype-selective biochemical tools and drugs.
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20 MeSH Terms
Molecular Mechanisms of GPCR Signaling: A Structural Perspective.
Gurevich VV, Gurevich EV
(2017) Int J Mol Sci 18:
MeSH Terms: Animals, Arrestins, Humans, Protein Domains, Receptors, G-Protein-Coupled, Signal Transduction
Show Abstract · Added March 14, 2018
G protein-coupled receptors (GPCRs) are cell surface receptors that respond to a wide variety of stimuli, from light, odorants, hormones, and neurotransmitters to proteins and extracellular calcium. GPCRs represent the largest family of signaling proteins targeted by many clinically used drugs. Recent studies shed light on the conformational changes that accompany GPCR activation and the structural state of the receptor necessary for the interactions with the three classes of proteins that preferentially bind active GPCRs, G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. Importantly, structural and biophysical studies also revealed activation-related conformational changes in these three types of signal transducers. Here, we summarize what is already known and point out questions that still need to be answered. Clear understanding of the structural basis of signaling by GPCRs and their interaction partners would pave the way to designing signaling-biased proteins with scientific and therapeutic potential.
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6 MeSH Terms
Heterologous phosphorylation-induced formation of a stability lock permits regulation of inactive receptors by β-arrestins.
Tóth AD, Prokop S, Gyombolai P, Várnai P, Balla A, Gurevich VV, Hunyady L, Turu G
(2018) J Biol Chem 293: 876-892
MeSH Terms: Angiotensin II, Animals, COS Cells, Cercopithecus aethiops, HEK293 Cells, Humans, Immunoblotting, Microscopy, Confocal, Mitogen-Activated Protein Kinases, Phosphorylation, Receptors, G-Protein-Coupled, beta-Arrestins
Show Abstract · Added March 14, 2018
β-Arrestins are key regulators and signal transducers of G protein-coupled receptors (GPCRs). The interaction between receptors and β-arrestins is generally believed to require both receptor activity and phosphorylation by GPCR kinases. In this study, we investigated whether β-arrestins are able to bind second messenger kinase-phosphorylated, but inactive receptors as well. Because heterologous phosphorylation is a common phenomenon among GPCRs, this mode of β-arrestin activation may represent a novel mechanism of signal transduction and receptor cross-talk. Here we demonstrate that activation of protein kinase C (PKC) by phorbol myristate acetate, G-coupled GPCR, or epidermal growth factor receptor stimulation promotes β-arrestin2 recruitment to unliganded AT angiotensin receptor (ATR). We found that this interaction depends on the stability lock, a structure responsible for the sustained binding between GPCRs and β-arrestins, formed by phosphorylated serine-threonine clusters in the receptor's C terminus and two conserved phosphate-binding lysines in the β-arrestin2 N-domain. Using improved FlAsH-based serine-threonine clusters β-arrestin2 conformational biosensors, we also show that the stability lock not only stabilizes the receptor-β-arrestin interaction, but also governs the structural rearrangements within β-arrestins. Furthermore, we found that β-arrestin2 binds to PKC-phosphorylated ATR in a distinct active conformation, which triggers MAPK recruitment and receptor internalization. Our results provide new insights into the activation of β-arrestins and reveal their novel role in receptor cross-talk.
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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12 MeSH Terms
Non-visual arrestins regulate the focal adhesion formation via small GTPases RhoA and Rac1 independently of GPCRs.
Cleghorn WM, Bulus N, Kook S, Gurevich VV, Zent R, Gurevich EV
(2018) Cell Signal 42: 259-269
MeSH Terms: Actin Cytoskeleton, Animals, Cell Adhesion, Cell Line, Cell Movement, Fibroblasts, Focal Adhesions, Gene Expression Regulation, Mice, Neuropeptides, Receptors, G-Protein-Coupled, Signal Transduction, beta-Arrestin 1, beta-Arrestin 2, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, rho GTP-Binding Proteins
Show Abstract · Added March 14, 2018
Arrestins recruit a variety of signaling proteins to active phosphorylated G protein-coupled receptors in the plasma membrane and to the cytoskeleton. Loss of arrestins leads to decreased cell migration, altered cell shape, and an increase in focal adhesions. Small GTPases of the Rho family are molecular switches that regulate actin cytoskeleton and affect a variety of dynamic cellular functions including cell migration and cell morphology. Here we show that non-visual arrestins differentially regulate RhoA and Rac1 activity to promote cell spreading via actin reorganization, and focal adhesion formation via two distinct mechanisms. Arrestins regulate these small GTPases independently of G-protein-coupled receptor activation.
Copyright © 2017 Elsevier Inc. All rights reserved.
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1 Members
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17 MeSH Terms
Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors.
Prokop S, Perry NA, Vishnivetskiy SA, Toth AD, Inoue A, Milligan G, Iverson TM, Hunyady L, Gurevich VV
(2017) Cell Signal 36: 98-107
MeSH Terms: Amino Acid Sequence, Animals, Arrestins, COS Cells, Cattle, Cercopithecus aethiops, Conserved Sequence, HEK293 Cells, Humans, Lysine, Mutant Proteins, Mutation, Protein Binding, Protein Structure, Secondary, Receptors, G-Protein-Coupled, Rhodopsin
Show Abstract · Added March 14, 2018
Non-visual arrestins interact with hundreds of different G protein-coupled receptors (GPCRs). Here we show that by introducing mutations into elements that directly bind receptors, the specificity of arrestin-3 can be altered. Several mutations in the two parts of the central "crest" of the arrestin molecule, middle-loop and C-loop, enhanced or reduced arrestin-3 interactions with several GPCRs in receptor subtype and functional state-specific manner. For example, the Lys139Ile substitution in the middle-loop dramatically enhanced the binding to inactive M muscarinic receptor, so that agonist activation of the M did not further increase arrestin-3 binding. Thus, the Lys139Ile mutation made arrestin-3 essentially an activation-independent binding partner of M, whereas its interactions with other receptors, including the β-adrenergic receptor and the D and D dopamine receptors, retained normal activation dependence. In contrast, the Ala248Val mutation enhanced agonist-induced arrestin-3 binding to the β-adrenergic and D dopamine receptors, while reducing its interaction with the D dopamine receptor. These mutations represent the first example of altering arrestin specificity via enhancement of the arrestin-receptor interactions rather than selective reduction of the binding to certain subtypes.
Copyright © 2017. Published by Elsevier Inc.
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2 Members
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16 MeSH Terms
Bile acids and bariatric surgery.
Albaugh VL, Banan B, Ajouz H, Abumrad NN, Flynn CR
(2017) Mol Aspects Med 56: 75-89
MeSH Terms: Animals, Bile Acids and Salts, Diabetes Mellitus, Type 2, Enterohepatic Circulation, Gastrectomy, Gastric Bypass, Gastrointestinal Microbiome, Gene Expression Regulation, Glucose, Homeostasis, Humans, Insulin Resistance, Obesity, Morbid, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Rodentia, Signal Transduction
Show Abstract · Added June 6, 2017
Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids. In this review we highlight how bile acids potentially contribute to improved lipid and glucose homeostasis, insulin sensitivity and energy expenditure after these procedures. The impact of altered bile acid levels in enterohepatic circulation is also associated with changes in gut microflora, which may further contribute to some of these beneficial effects. We highlight the beneficial effects of experimental surgical procedures in rodents that alter bile secretory flow without gastric restriction or altering nutrient flow. This information suggests a role for bile acids beyond dietary fat emulsification in altering whole body glucose and lipid metabolism strongly, and also suggests emerging roles for the activation of the bile acid receptors farnesoid x receptor (FXR) and G-protein coupled bile acid receptor (TGR5) in these improvements. The limitations of rodent studies and the current state of our understanding is reviewed and the potential effects of bile acids mediating the short- and long-term metabolic improvements after bariatric surgery is critically examined.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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3 Members
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17 MeSH Terms
The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1.
Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, Schumacher MA, Hamilton KE, Lau KS, Shroyer NF, Frey MR
(2017) Cell Death Differ 24: 855-865
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Communication, Cell Count, Cell Differentiation, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Regulation, HT29 Cells, Humans, Ileum, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Paneth Cells, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-3, Receptors, G-Protein-Coupled, Stem Cell Niche, Stem Cells
Show Abstract · Added October 16, 2018
Paneth cells (PCs), a secretory population located at the base of the intestinal crypt, support the intestinal stem cells (ISC) with growth factors and participate in innate immunity by releasing antimicrobial peptides, including lysozyme and defensins. PC dysfunction is associated with disorders such as Crohn's disease and necrotizing enterocolitis, but the specific pathways regulating PC development and function are not fully understood. Here we tested the role of the neuregulin receptor ErbB3 in control of PC differentiation and the ISC niche. Intestinal epithelial ErbB3 knockout caused precocious appearance of PCs as early as postnatal day 7, and substantially increased the number of mature PCs in adult mouse ileum. ErbB3 loss had no effect on other secretory lineages, but increased expression of the ISC marker Lgr5. ErbB3-null intestines had elevated levels of the Atoh1 transcription factor, which is required for secretory fate determination, while Atoh1 cells had reduced ErbB3, suggesting reciprocal negative regulation. ErbB3-null intestinal progenitor cells showed reduced activation of the PI3K-Akt and ERK MAPK pathways. Inhibiting these pathways in HT29 cells increased levels of ATOH1 and the PC marker LYZ. Conversely, ErbB3 activation suppressed LYZ and ATOH1 in a PI3K-dependent manner. Expansion of the PC compartment in ErbB3-null intestines was accompanied with elevated ER stress and inflammation markers, raising the possibility that negative regulation of PCs by ErbB3 is necessary to maintain homeostasis. Taken together, our data suggest that ErbB3 restricts PC numbers through PI3K-mediated suppression of Atoh1 levels leading to inhibition of PC differentiation, with important implications for regulation of the ISC niche.
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MeSH Terms
Unique Cellular Lineage Composition of the First Gland of the Mouse Gastric Corpus.
O'Neil A, Petersen CP, Choi E, Engevik AC, Goldenring JR
(2017) J Histochem Cytochem 65: 47-58
MeSH Terms: Animals, Clusterin, Gastric Mucosa, Male, Mice, Mice, Inbred C57BL, Mucin-4, Parietal Cells, Gastric, Plant Lectins, Protein-Serine-Threonine Kinases, Receptors, G-Protein-Coupled, SOXB1 Transcription Factors, Stem Cells, Stomach
Show Abstract · Added April 18, 2017
The glandular stomach has two major zones: the acid secreting corpus and the gastrin cell-containing antrum. Nevertheless, a single gland lies at the transition between the forestomach and corpus in the mouse stomach. We have sought to define the lineages that make up this gland unit at the squamocolumnar junction. The first gland in mice showed a notable absence of characteristic corpus lineages, including parietal cells and chief cells. In contrast, the gland showed strong staining of Griffonia simplicifolia-II (GSII)-lectin-positive mucous cells at the bases of glands, which were also positive for CD44 variant 9 and Clusterin. Prominent numbers of doublecortin-like kinase 1 (DCLK1) positive tuft cells were present in the first gland. The first gland contained Lgr5-expressing putative progenitor cells, and a large proportion of the cells were positive for Sox2. The cells of the first gland stained strongly for MUC4 and EpCAM, but both were absent in the normal corpus mucosa. The present studies indicate that the first gland in the corpus represents a unique anatomic entity. The presence of a concentration of progenitor cells and sensory tuft cells in this gland suggests that it may represent a source of reserve reparative cells for adapting to severe mucosal damage.
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14 MeSH Terms