DOCSLIB.ORG

The Anti-Inflammatory Function of HDL Is Impaired in Type 2 Diabetes

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Anti-Inflammatory Function of HDL Is Impaired in Type 2 Diabetes Ebtehaj et al. Cardiovasc Diabetol (2017) 16:132 DOI 10.1186/s12933-017-0613-8 Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access The anti‑infammatory function of HDL is impaired in type 2 diabetes: role of hyperglycemia, paraoxonase‑1 and low grade infammation Sanam Ebtehaj1, Eke G. Gruppen2, Mojtaba Parvizi3, Uwe J. F. Tietge1*† and Robin P. F. Dullaart2† Abstract Background: Functional properties of high density lipoproteins (HDL) are increasingly recognized to play a physi- ological role in atheroprotection. Type 2 diabetes mellitus (T2DM) is characterized by low HDL cholesterol, but the efect of chronic hyperglycemia on the anti-infammatory capacity of HDL, a metric of HDL function, is unclear. There- fore, the aim of the present study was to establish the impact of T2DM on the HDL anti-infammatory capacity, taking paraoxonase-1 (PON-1) activity and low grade infammation into account. Methods: The HDL anti-infammatory capacity, determined as the ability to suppress tumor necrosis factor-α (TNF-α) induced vascular cell adhesion molecule-1 (VCAM-1) mRNA expression in endothelial cells in vitro (higher values indicate lower anti-infammatory capacity), PON-1 (arylesterase) activity, hs-C-reactive protein (hs-CRP), serum amyloid A (SAA) and TNF-α were compared in 40 subjects with T2DM (no insulin or statin treatment) and 36 non-diabetic subjects. Results: T2DM was associated with impaired HDL anti-infammatory capacity (3.18 vs 1.05 fold increase in VCAM-1 mRNA expression; P < 0.001), coinciding with decreased HDL cholesterol (P 0.001), apolipoprotein A-I (P 0.038) and PON-1 activity (P 0.023), as well as increased hs-CRP (P 0.043) and TNF-α= (P 0.005). In all subjects= combined, age- and sex-adjusted= multivariable linear regression analysis =demonstrated that impaired= HDL anti-infammatory capacity was associated with hyperglycemia (β 0.499, P < 0.001), lower PON-1 activity (β 0.192, P 0.030) and higher hs-CRP (β 0.220, P 0.016). = = − = = = Conclusions: The HDL anti-infammatory capacity is substantially impaired in T2DM, at least partly attributable to the degree of hyperglycemia, decreased PON-1 activity and enhanced low grade chronic infammation. Decreased anti- infammatory protection capacity of HDL conceivably contributes to the increased atherosclerosis risk associated with T2DM. Keywords: High sensitivity C-reactive protein, High density lipoprotein function, Paraoxonase-1, Serum amyloid A, Type 2 diabetes mellitus Introduction disease (CVD) [1]. Tis elevated CVD risk has been, at Patients with type 2 diabetes mellitus (T2DM) have a sub- least in part, attributed to the low high density lipo- stantially increased risk of atherosclerotic cardiovascular protein (HDL) cholesterol levels consistently found in patients with insulin resistance and T2DM [2–4]. How- *Correspondence: [email protected] ever, data from genetic as well as pharmacological inter- †Uwe J. F. Tietge and Robin P. F. Dullaart contributed equally to this work vention studies now suggest that HDL cholesterol levels 1 Department of Pediatrics, University of Groningen, University Medical per se might not be as relevant as a predictive biomarker Center Groningen, Hanzeplein 1, 9713GZ Groningen, The Netherlands Full list of author information is available at the end of the article of atherosclerosis as previously thought [5–7]. Instead, © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ebtehaj et al. Cardiovasc Diabetol (2017) 16:132 Page 2 of 9 the functionality of HDL particles could have a more according to guidelines from the Dutch College of Gen- pathophysiologically important impact [8, 9], together eral Practitioners (fasting plasma glucose ≥ 7.0 mmol/L; with determinations of HDL subpopulations and HDL non-fasting plasma glucose ≥ 11.1 mmol/L). Subjects particle numbers [10–14]. HDL may slow the process of with a history of CVD, chronic kidney disease (estimated atherogenesis by several important biological proper- glomerular fltration rate < 60 mL/min/1.73 m2 and/or ties. First, HDL promotes cholesterol efux and reverse proteinuria), liver function abnormalities or thyroid dys- cholesterol transport, thereby removing cholesterol from function, as well as current smokers and subjects who macrophage foam cells in atherosclerotic lesions [8, 9]. used lipid lowering drugs were also excluded. Te use of Variable results have been reported on the impact of dia- metformin, sulfonylurea and antihypertensive medica- betes on HDL-mediated cholesterol efux capacity, likely tion was allowed, but insulin use was an exclusion crite- due to diferent assay conditions employed and refect- rion. Blood pressure was measured after 15 min rest at ing the infuence of the severity of hyperglycemia [15– the left arm in sitting position using a sphygmomanom- 17]. In a recent cross-sectional analysis of the CODAM eter. Body mass index (BMI in kg/m2) was calculated as study including 552 subjects we did not fnd evidence weight divided by height squared. Waist circumference that moderate hyperglycemia as such impairs cholesterol was measured between the 10th rib and the iliac crest. efux capacity [17]. Second, HDL can inhibit the oxida- Te metabolic syndrome (MetS) was defned according tion of native LDL thereby preventing the formation of to the revised NCEP-ATP III criteria [27]. Tree or more pro-atherosclerotic and pro-infammatory LDL particles of the following criteria were required for categorization [18]. Also for the efect of T2DM on the anti-oxidative of subjects with MetS: waist circumference > 102 cm for capacity of HDL opposing data have been reported. men and > 88 cm for women, hypertension (blood pres- In some studies, HDL from T2DM patients exhibited sure ≥ 130/85 mmHg or use of antihypertensive medica- a reduced capacity to protect low density lipoproteins tion), fasting plasma triglycerides ≥ 1.70 mmol/L; HDL (LDL) from oxidation [19–21], whereas we found previ- cholesterol < 1.0 mmol/L for men and < 1.3 mmol/L for ously that the anti-oxidative capacity of HDL is impaired women, fasting glucose ≥ 5.6 mmol/L, or previously in T2DM but only taking account of the diabetes-asso- diagnosed T2DM. Te participants were studied after an ciated decrease in HDL cholesterol [22]. Again, these overnight fast. diferences might be related to the degree of metabolic control in the T2DM patients studied. Tird, HDL has Laboratory analyses potent anti-infammatory activity and can reduce, e.g. Serum and EDTA-anticoagulated plasma samples were endothelial activation [8, 9, 23], thus also interfering stored at − 80 °C until analysis. Plasma glucose was with an early step of atherogenesis. Notably, the anti- measured shortly after blood collection with an APEC infammatory capacity of HDL was found to be impaired glucose analyzer (APEC Inc., Danvers, MA, USA). in acute myocardial infarction patients [24–26], and to Total cholesterol and triglycerides were measured by predict recurrent CVD events even independent of HDL routine enzymatic methods (Roche/Hitachi Cat. Nos cholesterol and apolipoprotein (apo) A-I, the class-defn- 11875540 and 1187602, respectively; Roche Diagnos- ing apolipoprotein of HDL [25]. Much less is currently tics GmBH, Mannheim, Germany). HDL cholesterol known about the potential efect of T2DM specifcally on was assayed by a homogeneous enzymatic colorimetric the anti-infammatory properties of HDL. test (Roche/Hitachi, Cat. No 04713214). Non-HDL cho- In the present cross-sectional study we tested the lesterol was calculated as the diference between total hypothesis that the anti-infammatory function of HDL cholesterol and HDL cholesterol. LDL cholesterol was is impaired in T2DM. Furthermore, we aimed to deline- calculated by the Friedewald formula if triglycerides were ate the relationship of this metric of HDL function with < 4.5 mmol/L. Apolipoprotein A-I (apoA-I) and apolipo- hyperglycemia, PON-1 activity and low grade chronic protein B (apoB) were measured by immunoturbidim- infammation markers. etry (Roche/Cobas Integra Tinaquant Cat No. 03032566, Roche Diagnostics). Glycated hemoglobin (HbA1c) was Methods measured by high-performance liquid chromatography Subjects (Bio-Rad, Veenendaal, the Netherlands; normal range: Te study protocol was approved by the medical eth- 27–43 mmol/mol). ics committee of the University Medical Center Gron- Serum paraoxonase-1 (PON-1) enzymatic activity was ingen. Men and women with and without T2DM, aged measured as arylesterase activity, i.e. as the rate of hydrol- > 18 years, were recruited by advertisement in local news- ysis of phenyl acetate into phenol [28, 29]. Arylesterase papers. Tey participated after written informed consent activity, measured with this assay, is positively correlated had been obtained. T2DM had been diagnosed previously with PON-1 enzymatic activity toward paraoxon [30]. Ebtehaj et al. Cardiovasc Diabetol (2017) 16:132 Page 3 of 9 High sensitivity C-reactive protein (hs-CRP) was anti-infammatory capacity. In addition, under the assay assayed by
Load more

Recommended publications
  • Genome-Wide Association Study of Increasing Suicidal Ideation During Antidepressant Treatment in the GENDEP Project
    The Pharmacogenomics Journal (2012) 12, 68–77 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project NPerroud1,2,3,RUher1, Suicidal thoughts during antidepressant treatment have been the focus of 1 2,3,4 several candidate gene association studies. The aim of the present genome- MYM Ng , M Guipponi , wide association study was to identify additional genetic variants involved in 5 6 JHauser, N Henigsberg , increasing suicidal ideation during escitalopram and nortriptyline treatment. WMaier7,OMors8, A total of 706 adult participants of European ancestry, treated for major M Gennarelli9, M Rietschel10, depression with escitalopram or nortriptyline over 12 weeks in the Genome- DSouery11, MZ Dernovsek12, Based Therapeutic Drugs for Depression (GENDEP) study were genotyped 13 14 with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). AS Stamp ,MLathrop , A total of 244 subjects experienced an increase in suicidal ideation AFarmer1, G Breen1,KJAitchison1, during follow-up. The genetic marker most significantly associated with CM Lewis1,IWCraig1 increasing suicidality (8.28 Â 10À7) was a single-nucleotide polymorphism and P McGuffin1 (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific 1MRC Social, Genetic and Developmental Psychiatry associations within KCNIP4 (Kv channel-interacting protein 4; chromosome Centre, Institute of Psychiatry, King’s College 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome London, London, UK; 2Department of Psychiatry, 8p21.1) were found in subjects treated with escitalopram.
    [Show full text]
  • Identification of the Binding Partners for Hspb2 and Cryab Reveals
    Brigham Young University BYU ScholarsArchive Theses and Dissertations 2013-12-12 Identification of the Binding arP tners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non- Redundant Roles for Small Heat Shock Proteins Kelsey Murphey Langston Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Microbiology Commons BYU ScholarsArchive Citation Langston, Kelsey Murphey, "Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins" (2013). Theses and Dissertations. 3822. https://scholarsarchive.byu.edu/etd/3822 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston A thesis submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Master of Science Julianne H. Grose, Chair William R. McCleary Brian Poole Department of Microbiology and Molecular Biology Brigham Young University December 2013 Copyright © 2013 Kelsey Langston All Rights Reserved ABSTRACT Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactors and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston Department of Microbiology and Molecular Biology, BYU Master of Science Small Heat Shock Proteins (sHSP) are molecular chaperones that play protective roles in cell survival and have been shown to possess chaperone activity.
    [Show full text]
  • A Gene Expression Resource Generated by Genome-Wide Lacz
    © 2015. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2015) 8, 1467-1478 doi:10.1242/dmm.021238 RESOURCE ARTICLE A gene expression resource generated by genome-wide lacZ profiling in the mouse Elizabeth Tuck1,**, Jeanne Estabel1,*,**, Anika Oellrich1, Anna Karin Maguire1, Hibret A. Adissu2, Luke Souter1, Emma Siragher1, Charlotte Lillistone1, Angela L. Green1, Hannah Wardle-Jones1, Damian M. Carragher1,‡, Natasha A. Karp1, Damian Smedley1, Niels C. Adams1,§, Sanger Institute Mouse Genetics Project1,‡‡, James N. Bussell1, David J. Adams1, Ramiro Ramırez-Soliś 1, Karen P. Steel1,¶, Antonella Galli1 and Jacqueline K. White1,§§ ABSTRACT composite of RNA-based expression data sets. Strong agreement was observed, indicating a high degree of specificity in our data. Knowledge of the expression profile of a gene is a critical piece of Furthermore, there were 1207 observations of expression of a information required to build an understanding of the normal and particular gene in an anatomical structure where Bgee had no essential functions of that gene and any role it may play in the data, indicating a large amount of novelty in our data set. development or progression of disease. High-throughput, large- Examples of expression data corroborating and extending scale efforts are on-going internationally to characterise reporter- genotype-phenotype associations and supporting disease gene tagged knockout mouse lines. As part of that effort, we report an candidacy are presented to demonstrate the potential of this open access adult mouse expression resource, in which the powerful resource. expression profile of 424 genes has been assessed in up to 47 different organs, tissues and sub-structures using a lacZ reporter KEY WORDS: Gene expression, lacZ reporter, Mouse, Resource gene.
    [Show full text]
  • The Role of High Density Lipoprotein Compositional and Functional Heterogeneity in Metabolic Disease
    The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease By Scott M. Gordon B.S. State University of New York College at Brockport October, 2012 A Dissertation Presented to the Faculty of The University of Cincinnati College of Medicine in partial fulfillment of the requirements for the Degree of Doctor of Philosophy from the Pathobiology and Molecular Medicine graduate program W. Sean Davidson Ph.D. (Chair) David Askew Ph.D. Professor and Thesis Chair Professor Department of Pathology Department of Pathology University of Cincinnati University of Cincinnati Francis McCormack M.D. Gangani Silva Ph.D. Professor Assistant Professor Department of Pathology Department of Pathology University of Cincinnati University of Cincinnati Jason Lu Ph.D. Assistant Professor Division of Bioinformatics Cincinnati Children’s Hospital i Abstract High density lipoproteins (HDL) are complexes of phospholipid, cholesterol and protein that circulate in the blood. Epidemiological studies have demonstrated a strong inverse correlation between plasma levels of HDL associated cholesterol (HDL-C) and the incidence of cardiovascular disease (CVD). Clinically, HDL-C is often measured and used in combination with low density lipoprotein cholesterol (LDL-C) to assess overall cardiovascular health. HDL have been shown to possess a wide variety of functional attributes which likely contribute to this protection including anti-inflammatory and anti- oxidative properties and the ability to remove excess cholesterol from peripheral tissues and deliver it to the liver for excretion, a process known as reverse cholesterol transport. This functional diversity might be explained by the complexity of HDL composition. Recent studies have taken advantage of advances in mass spectrometry technologies to characterize the proteome of total HDL finding that over 50 different proteins can associate with these particles.
    [Show full text]
  • Research Article Characterization of the Equine Skeletal Muscle
    McGivney et al. BMC Genomics 2010, 11:398 http://www.biomedcentral.com/1471-2164/11/398 RESEARCH ARTICLE Open Access CharacterizationResearch article of the equine skeletal muscle transcriptome identifies novel functional responses to exercise training Beatrice A McGivney1, Paul A McGettigan1, John A Browne1, Alexander CO Evans1,3, Rita G Fonseca2, Brendan J Loftus3, Amanda Lohan3, David E MacHugh1,3, Barbara A Murphy1, Lisa M Katz2 and Emmeline W Hill*1 Abstract Background: Digital gene expression profiling was used to characterize the assembly of genes expressed in equine skeletal muscle and to identify the subset of genes that were differentially expressed following a ten-month period of exercise training. The study cohort comprised seven Thoroughbred racehorses from a single training yard. Skeletal muscle biopsies were collected at rest from the gluteus medius at two time points: T1 - untrained, (9 ± 0.5 months old) and T2 - trained (20 ± 0.7 months old). Results: The most abundant mRNA transcripts in the muscle transcriptome were those involved in muscle contraction, aerobic respiration and mitochondrial function. A previously unreported over-representation of genes related to RNA processing, the stress response and proteolysis was observed. Following training 92 tags were differentially expressed of which 74 were annotated. Sixteen genes showed increased expression, including the mitochondrial genes ACADVL, MRPS21 and SLC25A29 encoded by the nuclear genome. Among the 58 genes with decreased expression, MSTN, a negative regulator of muscle growth, had the greatest decrease. Functional analysis of all expressed genes using FatiScan revealed an asymmetric distribution of 482 Gene Ontology (GO) groups and 18 KEGG pathways.
    [Show full text]
  • Microarray Analysis Provides New Insights Into the Function of Apolipoprotein O in Hepg2 Cell Line Chen-Lu Wu, Shui-Ping Zhao* and Bi-Lian Yu*
    Wu et al. Lipids in Health and Disease 2013, 12:186 http://www.lipidworld.com/content/12/1/186 RESEARCH Open Access Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line Chen-Lu Wu, Shui-Ping Zhao* and Bi-Lian Yu* Abstract Background: Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells. Methods: HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR. Results: ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection.
    [Show full text]
  • Chromosome Inactivation
    bioRxiv preprint doi: https://doi.org/10.1101/079830; this version posted October 9, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Submission: GENETICS 4 Oct 2016 _______________________________________________________________________________ Single Cell Expression Data Reveal Human Genes that Escape X- Chromosome Inactivation Kerem Wainer-Katsir and Michal Linial* Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, ISRAEL 1 bioRxiv preprint doi: https://doi.org/10.1101/079830; this version posted October 9, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. * Corresponding author Prof. Michal Linial, Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, ISRAEL Telephone: +972-2-6584884; +972-54-8820035; FAX: 972-2-6523429 KWK: [email protected] ML: [email protected] Running title: Human X-inactivation escapee genes Keywords: X-inactivation, Allelic bias, RNA-seq, Escapees, single-cell Tables 1-3 Figures 1-6 Supplementary materials: Tables: S1-S8 Figures: S1-S2 2 bioRxiv preprint doi: https://doi.org/10.1101/079830; this version posted October 9, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Identification and Characterization of Membrane Proteins from Mouse
    ics om & B te i ro o P in f f o o r l m a Journal of a n t r i Dung et al., J Proteomics Bioinform 2013, 6:6 c u s o J DOI: 10.4172/jpb.1000272 ISSN: 0974-276X Proteomics & Bioinformatics Research Article Article OpenOpen Access Access Identification and Characterization of Membrane Proteins from Mouse Brain Tissue Nguyen Tien Dung, Do Huu Chi, Le Thi Bich Thao, Nguyen Thi Kim Dung, Nguyen Bich Nhi and Phan Van Chi* Institute of Biotechnology (IBT), Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet Rd, hanoi, Vietnam Abstract Membrane proteins are attractive targets for proteomics research because of their vital roles in numerous processes of the cell including: cell adhesion, immune response, metabolism and signal transduction... At the start of proteomics research, two-dimensional gel electrophoresis (2D-PAGE) was routinely used to separate complex proteomic samples. However, this method faces difficulties in separating membrane proteins due to their hydrophobicity. In this study, mouse brain membrane fractions were prepared using carbonate extraction and ultracentrifugation. The separation and identification of the membrane proteins by using a gel-based approach in combination with two-dimensional nano liquid chromatography coupled online with tandem mass spectrometry (2DNanoLC-Q-TOF-MS/MS) were presented. In total, 298 identified membrane proteins from mouse brain tissues were verified and predicted by UniProt database, SOSUI and TMHMM algorithms. Among them, 129 (43.3%) proteins that have at least one transmembrane domain were predicted by SOSUI and TMHMM. Furthermore, the function, subcellular location and hydrophobicity value of the identified membrane proteins were also categorized.
    [Show full text]
  • Photoreceptor-Induced RPE Phagolysosomal
    www.nature.com/scientificreports OPEN Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Received: 8 February 2018 Accepted: 28 March 2018 Maculopathy (STGD3) Published: xx xx xxxx Camille Dejos1, Sharee Kuny1, Woo Hyun Han1, Heather Capel2, Hélène Lemieux3 & Yves Sauvé1,2 For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the frst cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by photoreceptors is associated with defects in the underlying retinal pigment epithelium (RPE). To examine how photoreceptors exert cytotoxic efects on RPE cells, transgenic ELOVL4 (TG1–2 line; TG) and wild-type (WT) littermates were studied one month prior (preclinical stage) to onset of photoreceptor loss (two months). TG photoreceptor outer segments presented to human RPE cells are recognized and internalized into phagosomes, but their digestion is delayed. Live RPE cell imaging pinpoints decreased numbers of acidifed phagolysomes. In vivo, master regulator of lysosomal genes, transcription factor EB (TFEB), and key lysosomal enzyme Cathepsin D are both unafected. Oxidative stress, as ruled out with high-resolution respirometry, does not play a role at such an early stage. Upregulation of CRYBA1/A3 and phagocytic cells (microglia/macrophages) interposed between RPE and photoreceptors support adaptive responses to processing delays. Impaired phagolysosomal maturation is observed in RPE of mice expressing human mutant ELOVL4 in their photoreceptors prior to photoreceptor death and associated vision loss. Mutations in ELOVL4, responsible for a dominant maculopathy (Stargardt-like, STGD3), lead to an enzymati- cally inactive truncated protein lacking its C-terminal endoplasmic reticulum retention signal1.
    [Show full text]
  • University of Groningen Novel Insights Into the Pathogenesis of Metabolic
    University of Groningen Novel insights into the pathogenesis of metabolic syndrome-related disease Boer, Jan Freark de IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2013 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Boer, J. F. D. (2013). Novel insights into the pathogenesis of metabolic syndrome-related disease. s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 Chapter 7 General Discussion Jan Freark de Boer Chapter 7 134 General discussion There’s an urgent need to increase our understanding of the metabolic syndrome The obesity epidemic is progressively affecting larger and larger parts of the world causing increasing healthcare problems and costs in many countries.
    [Show full text]
  • Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac Hspb2 Interactome
    RESEARCH ARTICLE Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome Julianne H. Grose1*, Kelsey Langston1, Xiaohui Wang2, Shayne Squires2,3, Soumyajit Banerjee Mustafi2, Whitney Hayes1, Jonathan Neubert1, Susan K. Fischer4, Matthew Fasano4, Gina Moore Saunders2, Qiang Dai3, Elisabeth Christians2,E. Douglas Lewandowski4, Peipei Ping5, Ivor J. Benjamin2,3* 1 Microbiology and Molecular Biology Department, Brigham Young University, Provo, UT, 84602, United States of America, 2 Laboratory of Cardiac Disease, Redox Signaling and Cell Regeneration, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, UT, 84132, United States of America, 3 Division of Cardiovascular Medicine, Dept. of Medicine, Medical College of Wisconsin, Milwaukee, WI, 53226, United States of America, 4 Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, University of Illinois at Chicago College of Medicine, Chicago, IL, 60612, United States of America, 5 UCLA Departments of Physiology, Medicine, and Cardiology, Los Angeles, CA, 90095, United States of America OPEN ACCESS * Citation: Grose JH, Langston K, Wang X, Squires S, [email protected] (JHG); [email protected] (IJB) Mustafi SB, Hayes W, et al. (2015) Characterization of the Cardiac Overexpression of HSPB2 Reveals Mitochondrial and Myogenic Roles Supported by a Cardiac HspB2 Interactome. PLoS ONE 10(10): Abstract e0133994. doi:10.1371/journal.pone.0133994 Small Heat Shock Proteins (sHSPs) are molecular chaperones that transiently interact with Editor: Harm H Kampinga, UMCG, NETHERLANDS other proteins, thereby assisting with quality control of proper protein folding and/or degra- Received: October 3, 2014 dation. They are also recruited to protect cells from a variety of stresses in response to Accepted: July 3, 2015 extreme heat, heavy metals, and oxidative-reductive stress.
    [Show full text]
  • Universidad Autónoma De Madrid
    Universidad Autónoma de Madrid Departamento de Bioquímica Identification of the substrates of the protease MT1-MMP in TNFα- stimulated endothelial cells by quantitative proteomics. Analysis of their potential use as biomarkers in inflammatory bowel disease. Agnieszka A. Koziol Tesis doctoral Madrid, 2013 2 Departamento de Bioquímica Facultad de Medicina Universidad Autónoma de Madrid Identification of the substrates of the protease MT1-MMP in TNFα- stimulated endothelial cells by quantitative proteomics. Analysis of their potential use as biomarkers in inflammatory bowel disease. Memoria presentada por Agnieszka A. Koziol licenciada en Ciencias Biológicas para optar al grado de Doctor. Directora: Dra Alicia García Arroyo Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, 2013 3 4 ACKNOWLEDGEMENTS - ACKNOWLEDGEMENTS - First and foremost I would like to express my sincere gratitude to my supervisor Dr. Alicia García Arroyo for giving me the great opportunity to study under her direction. Her encouragement, guidance and support from the beginning to the end, enabled me to develop and understand the subject. Her feedback to this manuscript, critical reading and corrections was inappreciable to finish this dissertation. Next, I would like to express my gratitude to those who helped me substantially along the way. To all members of MMPs’ lab, for their interest in the project, teaching me during al these years and valuable contribution at the seminary discussion. Without your help it would have not been possible to do some of those experiments. Thank you all for creating a nice atmosphere at work and for being so good friends in private. I would like to also thank all of the collaborators and technical units for their support and professionalism.
    [Show full text]