Role of Myeloperoxidase Mediated Oxidative Modification and Apolipoprotein Composition in High Density Lipoprotein Function
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Heterozygous ATP-Binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease
bioRxiv preprint doi: https://doi.org/10.1101/780734; this version posted September 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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 4.0 International license. Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease Short title: Heterozygous ABCG5 deficiency and risk of CAD Akihiro Nomura*, MD PhD, Connor A. Emdin*, DPhil, Hong Hee Won, PhD, Gina M. Peloso, PhD, Pradeep Natarajan, MD, Diego Ardissino, MD, John Danesh, FRCP DPhil, Heribert Schunkert, MD, Adolfo Correa, MD PhD, Matthew J. Bown, MD FRCS, Nilesh J. Samani, MD FRCP, Jeanette Erdmann, PhD, Ruth McPherson, MD, Hugh Watkins, MD PhD, Danish Saleheen, MD, Roberto Elosua, MD PhD, Masa-aki Kawashiri, MD PhD, Hayato Tada, MD PhD, Namrata Gupta, PhD, Svati H. Shah, MD MHS, Daniel J. Rader, MD, Stacey Gabriel, PhD, Amit V. Khera*, MD, Sekar Kathiresan*, MD *: These authors contributed equally Address for correspondence: Sekar Kathiresan, MD Verve Therapeutics 26 Landsdowne Street, 1st Floor Cambridge, MA 02139 Email: [email protected] Phone: 617 603 0070 bioRxiv preprint doi: https://doi.org/10.1101/780734; this version posted September 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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 4.0 International license. Abstract Background: Familial sitosterolemia is a rare, recessive Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. -
The Expression of the Human Apolipoprotein Genes and Their Regulation by Ppars
CORE Metadata, citation and similar papers at core.ac.uk Provided by UEF Electronic Publications The expression of the human apolipoprotein genes and their regulation by PPARs Juuso Uski M.Sc. Thesis Biochemistry Department of Biosciences University of Kuopio June 2008 Abstract The expression of the human apolipoprotein genes and their regulation by PPARs. UNIVERSITY OF KUOPIO, the Faculty of Natural and Environmental Sciences, Curriculum of Biochemistry USKI Juuso Oskari Thesis for Master of Science degree Supervisors Prof. Carsten Carlberg, Ph.D. Merja Heinäniemi, Ph.D. June 2008 Keywords: nuclear receptors; peroxisome proliferator-activated receptor; PPAR response element; apolipoprotein; lipid metabolism; high density lipoprotein; low density lipoprotein. Lipids are any fat-soluble, naturally-occurring molecules and one of their main biological functions is energy storage. Lipoproteins carry hydrophobic lipids in the water and salt-based blood environment for processing and energy supply in liver and other organs. In this study, the genomic area around the apolipoprotein genes was scanned in silico for PPAR response elements (PPREs) using the in vitro data-based computer program. Several new putative REs were found in surroundings of multiple lipoprotein genes. The responsiveness of those apolipoprotein genes to the PPAR ligands GW501516, rosiglitazone and GW7647 in the HepG2, HEK293 and THP-1 cell lines were tested with real-time PCR. The APOA1, APOA2, APOB, APOD, APOE, APOF, APOL1, APOL3, APOL5 and APOL6 genes were found to be regulated by PPARs in direct or secondary manners. Those results provide new insights in the understanding of lipid metabolism and so many lifestyle diseases like atherosclerosis, type 2 diabetes, heart disease and stroke. -
The Effect of Statin Treatment on Intratumoral Cholesterol Levels and LDL Receptor Expression: a Window-Of-Opportunity Breast Ca
Feldt et al. Cancer & Metabolism (2020) 8:25 https://doi.org/10.1186/s40170-020-00231-8 RESEARCH Open Access The effect of statin treatment on intratumoral cholesterol levels and LDL receptor expression: a window-of- opportunity breast cancer trial Maria Feldt1,2* , Julien Menard1, Ann H. Rosendahl1,2, Barbara Lettiero1, Pär-Ola Bendahl1, Mattias Belting1,2,3 and Signe Borgquist1,4 Abstract Background: Deregulated lipid metabolism is common in cancer cells and the mevalonate pathway, which synthesizes cholesterol, is central in lipid metabolism. This study aimed to assess statin-induced changes of the intratumoral levels of cholesterol and the expression of the low-density lipoprotein receptor (LDLR) to enhance our understanding of the role of the mevalonate pathway in cancer cholesterol metabolism. Methods: This study is based on a phase II clinical trial designed as a window-of-opportunity trial including 50 breast cancer patients treated with 80 mg of atorvastatin/day for 2 weeks, between the time of diagnosis and breast surgery. Lipids were extracted from frozen tumor tissue sampled pre- and post-atorvastatin treatment. Intratumoral cholesterol levels were measured using a fluorometric quantitation assay. LDLR expression was evaluated by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue. Paired blood samples pre- and post- atorvastatin were analyzed for circulating low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1, and apolipoprotein B. In vitro experiments on MCF-7 breast cancer cells treated with atorvastatin were performed for comparison on the cellular level. Results: In the trial, 42 patients completed all study parts. From the paired tumor tissue samples, assessment of the cholesterol levels was achievable for 14 tumors, and for the LDLR expression in 24 tumors. -
Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive Pulmonary Disease
International Journal of Molecular Sciences Review Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive Pulmonary Disease Stanislav Kotlyarov Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia; [email protected] Abstract: Chronic obstructive pulmonary disease (COPD) is the important medical and social problem. According to modern concepts, COPD is a chronic inflammatory disease, macrophages play a key role in its pathogenesis. Macrophages are heterogeneous in their functions, which is largely determined by their immunometabolic profile, as well as the features of lipid homeostasis, in which the ATP binding cassette transporter A1 (ABCA1) plays an essential role. The objective of this work is the analysis of the ABCA1 protein participation and the function of reverse cholesterol transport in the pathogenesis of COPD. The expression of the ABCA1 gene in lung tissues takes the second place after the liver, which indicates the important role of the carrier in lung function. The participation of the transporter in the development of COPD consists in provision of lipid metabolism, regulation of inflammation, phagocytosis, and apoptosis. Violation of the processes in which ABCA1 is involved may be a part of the pathophysiological mechanisms, leading to the formation of a heterogeneous clinical course of the disease. Keywords: chronic obstructive pulmonary disease; COPD; inflammation; ABCA1; reverse cholesterol transport; innate immune system Citation: Kotlyarov, S. Participation of ABCA1 Transporter in Pathogenesis of Chronic Obstructive 1. Introduction Pulmonary Disease. Int. J. Mol. Sci. Chronic obstructive pulmonary disease (COPD) is one of the most widespread dis- 2021, 22, 3334. https://doi.org/ eases, it has great medical significance due to the high frequency of temporary and per- 10.3390/ijms22073334 sistent disability and mortality. -
Proteomic Analysis of HDL from Inbred Mouse Strains Implicates APOE Associated with HDL in Reduced Cholesterol Effl Ux Capacity Via the ABCA1 Pathway
Supplemental Material can be found at: http://www.jlr.org/content/suppl/2015/12/15/jlr.M063701.DC1 .html ˔ Author’s Choice Proteomic analysis of HDL from inbred mouse strains implicates APOE associated with HDL in reduced cholesterol effl ux capacity via the ABCA1 pathway Nathalie Pamir , 1, * Patrick Hutchins , * Graziella Ronsein , * Tomas Vaisar , * Catherine A. Reardon , † Godfrey S. Getz , † Aldons J. Lusis , § and Jay W. Heinecke * Downloaded from Department of Medicine,* University of Washington , Seattle, WA ; Department of Pathology, † University of Chicago , Chicago, IL ; and Department of Genetics, § University of California at Los Angeles , Los Angeles, CA Abstract Cholesterol effl ux capacity associates strongly Supplementary key words atherosclerosis • cardiovascular risk • mass and negatively with the incidence and prevalence of human spectrometry • high density lipoprotein • apolipoprotein E • ATP bind- CVD. We investigated the relationships of HDL’s size and ing cassette transporter A1 www.jlr.org protein cargo with its cholesterol effl ux capacity using APOB-depleted serum and HDLs isolated from fi ve inbred mouse strains with different susceptibilities to atherosclero- Clinical and epidemiological studies show a robust at Univ of Washington Health Sciences Library SB-55, on February 5, 2016 sis. Like humans, mouse HDL carried >70 proteins linked to inverse association of HDL-cholesterol (HDL-C) levels lipid metabolism, the acute-phase response, proteinase inhi- with CVD risk ( 1 ). In randomized clinical trials, how- bition, and the immune system. HDL’s content of specifi c ever, two drugs, CETP inhibitors and niacin, that elevate proteins strongly correlated with its size and cholesterol ef- fl ux capacity, suggesting that its protein cargo regulates its HDL-C levels by different mechanisms, failed to reduce function. -
1 CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on A
Page 1 of 55 Diabetes CETP inhibition improves HDL function but leads to fatty liver and insulin resistance in CETP-expressing transgenic mice on a high-fat diet Lin Zhu1,2, Thao Luu2, Christopher H. Emfinger1,2, Bryan A Parks5, Jeanne Shi2,7, Elijah Trefts3, Fenghua Zeng4, Zsuzsanna Kuklenyik5, Raymond C. Harris4, David H. Wasserman3, Sergio Fazio6 and John M. Stafford1,2,3,* 1VA Tennessee Valley Healthcare System, 2Division of Diabetes, Endocrinology, & Metabolism, 3Department of Molecular Physiology and Biophysics, 4Devision of Nephrology and Hypertension, Vanderbilt University School of Medicine. 5Division of Laboratory Sciences, Centers for Disease Control and Prevention. 6The Center for Preventive Cardiology at the Knight Cardiovascular Institute, Oregon Health & Science University. 7Trinity College of Art and Science, Duke University. * Address correspondence and request for reprints to: John. M. Stafford, 7445D Medical Research Building IV, Nashville, TN 37232-0475, phone (615) 936-6113, fax (615) 936- 1667 Email: [email protected] Running Title: CETP inhibition and insulin resistance Word Count: 5439 Figures: 7 Tables: 1 1 Diabetes Publish Ahead of Print, published online September 13, 2018 Diabetes Page 2 of 55 Abstract In clinical trials inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but doesn’t robustly improve cardiovascular outcomes. About 2/3 of trial participants were obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define if CETP inhibition has different effects depending on the presence of obesity, we performed short- term anacetrapib treatment in chow- and HFD-fed CETP-transgenic mice. -
An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma
Cleveland State University EngagedScholarship@CSU Mathematics Faculty Publications Mathematics Department 2-1-2014 An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma Ying Huang Cleveland Clinic Joseph A. DiDonato Cleveland State University, [email protected] Bruce S. Levison Cleveland Clinic Dave Schmitt Cleveland Clinic Lin Li Cleveland Clinic Follow this and additional works at: https://engagedscholarship.csuohio.edu/scimath_facpub Part of the Mathematics Commons See next page for additional authors How does access to this work benefit ou?y Let us know! Repository Citation Huang, Ying; DiDonato, Joseph A.; Levison, Bruce S.; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary S.; Gu, Xiaodong; Kadiyala, Chandra S.; Wang, Zeneng; Culley, Miranda K.; Hazen, Jennie E.; DiDonato, Anthony J.; Fu, Xiaoming; Berisha, Stela Z.; Peng, Daoquan; Nguyen, Truc T.; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; PLow, Edward F.; Fox, Paul L.; Gogonea, Valentin; Tang, W.H. Wilson; Parks, John S.; Fisher, Edward A.; Smith, Jonathan D.; and Hazen, Stanley L., "An Abundant Dysfunctional Apolipoprotein A1 in Human Atheroma" (2014). Mathematics Faculty Publications. 161. https://engagedscholarship.csuohio.edu/scimath_facpub/161 This Article is brought to you for free and open access by the Mathematics Department at EngagedScholarship@CSU. It has been accepted for inclusion in Mathematics Faculty Publications by an authorized administrator of EngagedScholarship@CSU. For more information, please contact [email protected]. Authors Ying Huang, Joseph A. DiDonato, Bruce S. Levison, Dave Schmitt, Lin Li, Yuping Wu, Jennifer Buffa, Timothy Kim, Gary S. Gerstenecker, Xiaodong Gu, Chandra S. Kadiyala, Zeneng Wang, Miranda K. Culley, Jennie E. -
Coexpression of ATP-Binding Cassette Proteins ABCG5 and ABCG8 Permits Their Transport to the Apical Surface
Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface Gregory A. Graf, … , Jonathan C. Cohen, Helen H. Hobbs J Clin Invest. 2002;110(5):659-669. https://doi.org/10.1172/JCI16000. Article Cardiology Mutations in either ATP-binding cassette (ABC) G5 or ABCG8 cause sitosterolemia, an autosomal recessive disorder of sterol trafficking. To determine the site of action of ABCG5 and ABCG8, we expressed recombinant, epitope-tagged mouse ABCG5 and ABCG8 in cultured cells. Both ABCG5 and ABCG8 underwent N-linked glycosylation. When either protein was expressed individually in cells, the N-linked sugars remained sensitive to Endoglycosidase H (Endo H). When ABCG5 and ABCG8 were coexpressed, the attached sugars were Endo H–resistant and neuraminidase-sensitive, indicating that the proteins were transported to the trans-Golgi complex. The mature, glycosylated forms of ABCG5 and ABCG8 coimmunoprecipitated, consistent with heterodimerization of these two proteins. The Endo H–sensitive forms of ABCG5 and ABCG8 were confined to the endoplasmic reticulum (ER), whereas the mature forms were present in non-ER fractions in cultured hepatocytes. Immunoelectron microscopy revealed ABCG5 and ABCG8 on the plasma membrane of these cells. In polarized WIF-B cells, recombinant ABCG5 localized to the apical (canalicular) membrane when coexpressed with ABCG8, but not when expressed alone. To our knowledge this is the first direct demonstration that trafficking of an ABC half-transporter to the cell surface requires the presence of its dimerization partner. Find the latest version: https://jci.me/16000/pdf Coexpression of ATP-binding cassette See the related Commentary beginning on page 605. -
Biomolecules
biomolecules Review High-Density Lipoproteins Are Bug Scavengers Olivier Meilhac 1,2,*, Sébastien Tanaka 1,3 and David Couret 1,4 1 Université de la Réunion, Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), F-97490 Sainte-Clotilde, France; [email protected] (S.T.); [email protected] (D.C.) 2 CHU de La Réunion, Centre d’Investigations Clinique 1410, 97410 Saint-Pierre, France 3 AP-HP, Service d’Anesthésie-Réanimation, CHU Bichat-Claude Bernard, 75018 Paris, France 4 CHU de La Réunion, Neurocritical Care Unit, 97410 Saint-Pierre, France * Correspondence: [email protected]; Tel.: +33-262-93-88-11 Received: 7 March 2020; Accepted: 6 April 2020; Published: 12 April 2020 Abstract: Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol transporter could be challenged. All lipoproteins are reported to bind and potentially neutralize bacterial lipopolysaccharides (LPS); this is particularly true for HDL particles. In addition, HDL levels are drastically decreased under infectious conditions such as sepsis, suggesting a potential role in the clearance of bacterial material and, particularly, LPS. Moreover, “omics” technologies have unveiled significant changes in HDL composition in different inflammatory states, ranging from acute inflammation occurring during septic shock to low-grade inflammation associated with moderate endotoxemia such as periodontal disease or obesity. In this review, we will discuss HDL modifications associated with exposure to pathogens including bacteria, viruses and parasites, with a special focus on sepsis and the potential of HDL therapy in this context. -
Identification of Sequence Variations in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels
FULL LENGTH Iranian Biomedical Journal 20(2): 84-90 April 2016 Identification of Sequence Variations in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels Fatemeh Bandarian1,2, Maryam Sadat Daneshpour3, Mehdi Hedayati3, Mohsen Naseri4 and Fereidoun Azizi*3 1Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; 2Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran; 3Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Genomic Research Center, Birjand University of Medical Sciences, Birjand, Iran Received 29 November 2014; revised 19 April 2015; accepted 20 April 2015 ABSTRACT Background: Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level. Methods: This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (≤5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (≥95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing. Results: Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. -
Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus the DCCT/EDIC Study
Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus The DCCT/EDIC Study Baohai Shao, Leila R. Zelnick, Jake Wimberger, Jonathan Himmelfarb, John Brunzell, W. Sean Davidson, Janet K. Snell-Bergeon, Karin E. Bornfeldt, Ian H. de Boer, Jay W. Heinecke, for the DCCT/EDIC Research Group Objective—Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results—In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate (P<10−6). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43–0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40–0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions—Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. -
Association Between the APOA2 Rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI
biomedicines Article Association between the APOA2 rs3813627 Single Nucleotide Polymorphism and HDL and APOA1 Levels Through BMI Hatim Boughanem 1 , Borja Bandera-Merchán 2, Pablo Hernández-Alonso 2,3,4 , Noelia Moreno-Morales 5, Francisco José Tinahones 2,3, José Lozano 6 , Sonsoles Morcillo 2,3,* and Manuel Macias-Gonzalez 2,3,* 1 Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain; [email protected] 2 Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain; [email protected] (B.B.-M.); [email protected] (P.H.-A.); [email protected] (F.J.T.) 3 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERObn, 28029 Madrid, Spain 4 Human Nutrition Unit, Faculty of Medicine and Health Sciences, Sant Joan Hospital, Institut d’Investigació Sanitària Pere Virgili, Rovira i Virgili University, 43201 Reus, Spain 5 Department of Physiotherapy, School of Health Sciences, University of Malaga-Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; [email protected] 6 Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Málaga, 29010 Málaga, Spain; [email protected] * Correspondence: [email protected] (S.M.); [email protected] (M.M.-G.); Tel.: +34-951-032-648 (S.M. & M.M.-G.); Fax: +34-27-951-924-651 (S.M. & M.M.-G.) Received: 18 February 2020; Accepted: 25 February 2020; Published: 27 February 2020 Abstract: Background: The interaction between obesity and genetic traits on high density lipoprotein (HDL) levels has been extensively studied.