CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF-related diabetes (CFRD) is one of the most prevalent comorbidities of CF. Altered glucose homeostasis has been reported in CF patients. The mechanism has not been fully elucidated. Besides the consequence of pancreatic endocrine dysfunction, we focus on insulin-responsive tissues and glucose transportation to explain glucose homeostasis alteration in CFRD. Herein, we found that CFTR knockout mice exhibited insulin resistance and glucose tolerance. Furthermore, we demonstrated insulin-induced glucose transporter 4 (GLUT4) translocation to the cell membrane was abnormal in the CFTR knockout mice muscle fibers, suggesting that defective intracellular GLUT4 transportation may be the cause of impaired insulin responses and glucose homeostasis. We further demonstrated that PI(4,5)P2 could rescue CFTR related defective intracellular GLUT4 transportation, and CFTR could regulate PI(4,5)P2 cellular level through PIP5KA, suggesting PI(4,5)P2 is a down-stream signal of CFTR. Our results revealed a new signal mechanism of CFTR in GLUT4 translocation regulation, which helps explain glucose homeostasis alteration in CF patients.

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Altered glucose homeostasis in α2A-adrenoceptor knockout mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2004.10.023 ◽

2004 ◽

Vol 505 (1-3) ◽

pp. 243-252 ◽

Cited By ~ 33

Author(s):

Veronica Fagerholm ◽

Tove Grönroos ◽

Päivi Marjamäki ◽

Tapio Viljanen ◽

Mika Scheinin ◽

...

Keyword(s):

Glucose Homeostasis ◽

Knockout Mice ◽

Altered Glucose

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Cystic fibrosis transmembrane conductance regulator modulators for cystic fibrosis: a new dawn?

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-320680 ◽

2021 ◽

pp. archdischild-2020-320680

Author(s):

Claire Edmondson ◽

Christopher William Course ◽

Iolo Doull

Keyword(s):

Cystic Fibrosis ◽

Life Expectancy ◽

Respiratory Infections ◽

Autosomal Recessive Disorder ◽

Societal Implications ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Potent Effect ◽

Major Barrier ◽

Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is the most common life-limiting inherited condition in Caucasians. It is a multisystem autosomal recessive disorder caused by variants in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cell-surface localised chloride channel that regulates absorption and secretion of salt and water across epithelia. Until recently, the treatment for CF was predicated on ameliorating and preventing the downstream symptoms of CFTR dysfunction, primarily recurrent respiratory infections and pancreatic exocrine failure. But a new class of therapy—the CFTR modulators, which treat the basic defect and decrease the complications of CF, leads to significantly improved pulmonary function, decreased respiratory infections and improved nutrition. The newest agent, a combination of elexacaftor, tezacaftor and ivacaftor, will be suitable for approximately 90% of all people with CF and is likely to decrease the morbidity and significantly increase the life expectancy for most people with CF. The major barrier to their widespread introduction has been their cost, with many countries unwilling or unable to fund them. Nevertheless, such is their therapeutic efficacy and their likely potent effect on life expectancy that their advent has wider societal implications for the care of children and adults with CF.

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Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota

Gut Microbes ◽

10.4161/gmic.22430 ◽

2013 ◽

Vol 4 (1) ◽

pp. 41-47 ◽

Cited By ~ 60

Author(s):

Susan V. Lynch ◽

Katherine C. Goldfarb ◽

Yvette K. Wild ◽

Weidong Kong ◽

Robert C. De Lisle ◽

...

Keyword(s):

Cystic Fibrosis ◽

Knockout Mice ◽

Transmembrane Conductance Regulator ◽

Gastrointestinal Microbiota ◽

Transmembrane Conductance ◽

Cystic Fibrosis Transmembrane

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State of the Art on Approved Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators and Triple-Combination Therapy

Pharmaceuticals ◽

10.3390/ph14090928 ◽

2021 ◽

Vol 14 (9) ◽

pp. 928

Author(s):

Aniello Meoli ◽

Valentina Fainardi ◽

Michela Deolmi ◽

Giulia Chiopris ◽

Francesca Marinelli ◽

...

Keyword(s):

Cystic Fibrosis ◽

Young Children ◽

Autosomal Recessive Disorder ◽

Cftr Gene ◽

Transmembrane Conductance Regulator ◽

Inherited Disease ◽

Transmembrane Conductance ◽

Triple Combination Therapy ◽

Cystic Fibrosis Transmembrane ◽

Cftr Modulators

Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations, affecting approximately 80,000 people worldwide. CF is a complex multi-organ monogenic autosomal recessive disorder caused by a mutation in cystic fibrosis transmembrane conductance regulator (CFTR) gene. Since the discovery of the CFTR gene in 1989, more than 2000 mutations have been identified so far and about 240 can cause CF. Until recently, the treatment for CF was aimed to prevent and manage the manifestations of CFTR dysfunction, primarily recurrent pulmonary infections and pancreatic exocrine failure. Over the past few decades, the therapeutic approach to CF has been revolutionized by the development of a new class of small molecules called CFTR modulators that target specific defects caused by mutations in the CFTR gene. CFTR modulators have been shown to change profoundly the clinical course of the CF, leading to meaningful improvements in the lives of a large proportion of people of CF heterozygous for F508del, especially if started in young children. Further studies are needed to extend the use of triple CFTR modulation therapy also for young children in order to prevent the irreversible effects of the disease and for patients with very rare mutations with a personalized approach to treatment.

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A molecular atlas of proximal airway identifies subsets of known airway cell types revealing details of the unique molecular pathogenesis of Cystic Fibrosis

10.1101/2020.05.01.072876 ◽

2020 ◽

Author(s):

Gianni Carraro ◽

Justin Langerman ◽

Shan Sabri ◽

Zareeb Lorenzana ◽

Arunima Purkayastha ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Autosomal Recessive Disorder ◽

Cell Types ◽

Airway Disease ◽

Transmembrane Conductance Regulator ◽

Basal Cells ◽

Airway Epithelial ◽

Polarized Epithelia ◽

End Stage

Introduction/AbstractCystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts in excess of 70,000 people globally. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most significant determinant of morbidity and mortality. In this study we report results from a multi-institute consortium in which single cell transcriptomics were applied to define disease-related changes to the proximal airway of CF donors (n=19) undergoing transplantation for end-stage lung disease compared to the proximal airway of previously healthy lung donors (n=19). We found that all major airway epithelial cell types were conserved between control and CF donors. Disease-dependent differences were observed, including an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subtypes coupled with an unexpected decrease in cycling basal cells. This study developed a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

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New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach

Pharmaceuticals ◽

10.3390/ph13120445 ◽

2020 ◽

Vol 13 (12) ◽

pp. 445

Author(s):

Giada Righetti ◽

Monica Casale ◽

Michele Tonelli ◽

Nara Liessi ◽

Paola Fossa ◽

...

Keyword(s):

Cystic Fibrosis ◽

Molecular Docking ◽

Computational Study ◽

Autosomal Recessive Disorder ◽

Qsar Model ◽

Quantitative Structure Activity Relationship ◽

Docking Studies ◽

Van Der Waals Interactions ◽

Transmembrane Conductance Regulator ◽

Qsar Analysis

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators.

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Glucose transporters in the 21st Century

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00712.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. E141-E145 ◽

Cited By ~ 445

Author(s):

Bernard Thorens ◽

Mike Mueckler

Keyword(s):

21St Century ◽

Glucose Homeostasis ◽

Mammalian Cells ◽

Glucose Transporter ◽

Cellular Level ◽

Transport Proteins ◽

Whole Body ◽

Kinetic Properties ◽

Membrane Transport Proteins ◽

Physiological Substrates

The ability to take up and metabolize glucose at the cellular level is a property shared by the vast majority of existing organisms. Most mammalian cells import glucose by a process of facilitative diffusion mediated by members of the Glut (SLC2A) family of membrane transport proteins. Fourteen Glut proteins are expressed in the human and they include transporters for substrates other than glucose, including fructose, myoinositol, and urate. The primary physiological substrates for at least half of the 14 Glut proteins are either uncertain or unknown. The well-established glucose transporter isoforms, Gluts 1–4, are known to have distinct regulatory and/or kinetic properties that reflect their specific roles in cellular and whole body glucose homeostasis. Separate review articles on many of the Glut proteins have recently appeared in this journal. Here, we provide a very brief summary of the known properties of the 14 Glut proteins and suggest some avenues of future investigation in this area.

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Pseudomonas aeruginosa Alginate Promotes Burkholderia cenocepacia Persistence in Cystic Fibrosis Transmembrane Conductance Regulator Knockout Mice

Infection and Immunity ◽

10.1128/iai.01192-09 ◽

2010 ◽

Vol 78 (3) ◽

pp. 984-993 ◽

Cited By ~ 17

Author(s):

Sangbrita S. Chattoraj ◽

Rachana Murthy ◽

Shyamala Ganesan ◽

Joanna B. Goldberg ◽

Ying Zhao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Knockout Mice ◽

Bacterial Load ◽

Burkholderia Cenocepacia ◽

Respiratory Pathogen ◽

Transmembrane Conductance Regulator ◽

Transmembrane Conductance ◽

Innate Defense ◽

Cystic Fibrosis Transmembrane

ABSTRACT Pseudomonas aeruginosa, a major respiratory pathogen in cystic fibrosis (CF) patients, facilitates infection by other opportunistic pathogens. Burkholderia cenocepacia, which normally infects adolescent patients, encounters alginate elaborated by mucoid P. aeruginosa. To determine whether P. aeruginosa alginate facilitates B. cenocepacia infection in mice, cystic fibrosis transmembrane conductance regulator knockout mice were infected with B. cenocepacia strain BC7 suspended in either phosphate-buffered saline (BC7/PBS) or P. aeruginosa alginate (BC7/alginate), and the pulmonary bacterial load and inflammation were monitored. Mice infected with BC7/PBS cleared all of the bacteria within 3 days, and inflammation was resolved by day 5. In contrast, mice infected with BC7/alginate showed persistence of bacteria and increased cytokine levels for up to 7 days. Histological examination of the lungs indicated that there was moderate to severe inflammation and pneumonic consolidation in isolated areas at 5 and 7 days postinfection in the BC7/alginate group. Further, alginate decreased phagocytosis of B. cenocepacia by professional phagocytes both in vivo and in vitro. P. aeruginosa alginate also reduced the proinflammatory responses of CF airway epithelial cells and alveolar macrophages to B. cenocepacia infection. The observed effects are specific to P. aeruginosa alginate, because enzymatically degraded alginate or other polyuronic acids did not facilitate bacterial persistence. These observations suggest that P. aeruginosa alginate may facilitate B. cenocepacia infection by interfering with host innate defense mechanisms.

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