Nonglucuronidated Ezetimibe Disrupts CD13- and CD64-Coassembly in Membrane Microdomains and Decreases Cellular Cholesterol Content in Human Monocytes/Macrophages.
Atherosclerosis
/ genetics
Biological Transport
/ drug effects
CD13 Antigens
/ antagonists & inhibitors
Cholesterol
/ isolation & purification
Ezetimibe
/ pharmacology
Flow Cytometry
Glucuronates
/ genetics
Humans
Macrophages
/ metabolism
Membrane Microdomains
/ drug effects
Membrane Transport Proteins
/ genetics
Monocytes
/ metabolism
Receptors, IgG
/ antagonists & inhibitors
SOAT1
aminopeptidase-N
cholesterol processing
ezetimibe
raft
Journal
Cytometry. Part A : the journal of the International Society for Analytical Cytology
ISSN: 1552-4930
Titre abrégé: Cytometry A
Pays: United States
ID NLM: 101235694
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
01
02
2019
revised:
01
04
2019
accepted:
02
04
2019
pubmed:
18
4
2019
medline:
21
8
2020
entrez:
18
4
2019
Statut:
ppublish
Résumé
Ezetimibe (EZE) and glucuronidated EZE (EZE-Glu) differentially target Niemann-Pick C1-like 1 (NPC1L1) and CD13 (aminopeptidase-N) to inhibit intestinal cholesterol absorption and cholesterol processing in other cells, although the precise molecular mechanisms are not fully elucidated. Cellular effects of EZE, EZE-Glu, and the low-absorbable EZE-analogue S6130 were investigated on human monocyte-derived macrophages upon loading with atherogenic lipoproteins. EZE and S6130, but not EZE-Glu disturbed the colocalization of CD13 and its coreceptor CD64 (Fcγ receptor I) in membrane microdomains, and decreased the presence of both receptors in detergent-resistant membrane fractions. Biotinylated cholesterol absorption inhibitor C-5 (i.e., derivative of EZE) was rapidly internalized to perinuclear tubular structures of cells, resembling endoplasmic reticulum (ER), but CD13 was detected on extracellular sites of the plasma membrane and endolysosomal vesicles. Administration of EZE, but not of EZE-Glu or S6130, was associated with decreased cellular cholesteryl ester content, indicating the sterol-O acyltransferase 1 (SOAT1)-inhibition by EZE. Furthermore, EZE decreased the expression of molecules involved in cholesterol uptake and synthesis, in parallel with increased apolipoprotein A-I-mediated cholesterol efflux and upregulation of efflux-effectors. However, NPC1L1 the other claimed molecular target of EZE, was not detected in macrophages, thereby excluding this protein as target for EZE in macrophages. Thus, EZE is very likely a CD13-linked microdomain-disruptor and SOAT1-inhibitor in macrophages leading to in vitro anti-atherosclerotic effects through a decrease of net cellular cholesterol content. © 2019 International Society for Advancement of Cytometry.
Identifiants
pubmed: 30994973
doi: 10.1002/cyto.a.23772
doi:
Substances chimiques
Glucuronates
0
Membrane Transport Proteins
0
NPC1L1 protein, human
0
Receptors, IgG
0
Cholesterol
97C5T2UQ7J
CD13 Antigens
EC 3.4.11.2
Ezetimibe
EOR26LQQ24
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
869-884Informations de copyright
© 2019 International Society for Advancement of Cytometry.
Références
Clader JW. The discovery of ezetimibe: A view from outside the receptor. J Med Chem 2004;47:1-9.
Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, Suresh R, Sun S. Veltri EP on behalf of the Ezetimibe study group. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125-2534.
Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: A prospective, randomized, double-blind trial. Circulation 2003;107:2409-2415.
Sager PT, Capece R, Lipka L, Strony J, Yang B, Suresh R, Mitchel Y, Veltri EP. Effects of ezetimibe coadministered with simvastatin on C-reactive protein in a large cohort of hypercholesterolemic patients. Atherosclerosis 2005;179:361-367.
Landray M, Baigent C, Leaper C, Adu D, Altmann P, Armitage J, Ball S, Baxter A, Blackwell L, Cairns HS, et al. The second United Kingdom heart and renal protection (UK-HARP-II) study: A randomized controlled study of the biochemical safety and efficacy of adding ezetimibe to simvastatin as initial therapy among patients with CKD. Am J Kidney Dis 2006;47:385-395.
Davidson MH, Ballantyne CM, Kerzner B, Melani L, Sager PT, Lipka L, Strony J, Suresh R, Veltri EP, for the Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with statins: Randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia. Int J Clin Pract 2004;58:746-755.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397.
Bohula EA, Morrow DA, Giugliano RP, Blazing MA, He P, Park JG, Murphy SA, White JA, Kesaniemi YA, Pedersen TR, et al. Atherothrombotic risk stratification and ezetimibe for secondary prevention. J Am Coll Cardiol 2017;69:911-921.
Ghosal A, Hapangama N, Yuan Y, Achanfuo-Yeboah J, Iannucci R, Chowdhury S, Alton K, Patrick JE, Zbaida S. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos 2004;32:314-320.
van Heek M, Farley C, Compton DS, Hoos L, Alton KB, Sybertz EJ, Davis HR Jr. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br J Pharmacol 2000;129:1748-1754.
Oswald S, Giessmann T, Luetjohann D, Wegner D, Rosskopf D, Weitschies W, Siegmund W. Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins. Clin Pharmacol Ther 2006;80:477-485.
Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SPN, Maguire M, Golovko A, Zeng M, et al. Niemann-pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-1204.
Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, et al. The target of ezetimibe is Niemann-pick C1-like 1 (NPC1L1). Proc Natl Acad Sci USA 2005;102:8132-8137.
Kramer W, Girbig F, Corsiero D, Pfenninger A, Frick W, Jaehne G, Rhein M, Wendler W, Lottspeich F, Hochleitner EO, et al. Aminopeptidase N (CD13) is a molecular target of the cholesterol absorption inhibitor ezetimibe in the enterocyte brush border membrane. J Biol Chem 2005;280:1305-1320.
Mina-Osorio P. The moonlighting enzyme CD13: Old and new functions to target. Trends Mol Med 2008;14:361-371.
Licona-Limón I, Garay-Canales CA, Muñoz-Paleta O, Ortega E. CD13 mediates phagocytosis in human monocytic cells. J Leukoc Biol 2015;98:85-98.
Mendoza-Coronel E, Ortega E. Macrophage polarization modulates FcγR- and CD13-mediated phagocytosis and reactive oxygen species production, independently of receptor membrane expression. Front Immunol 2017;8:303.
Lindgren FT, Adamson GL, Jenson LC, Wood PD. Lipid and lipoprotein measurements in a normal adult American population. Lipids 1975;10:750-756.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-275.
Grandl M, Bared SM, Liebisch G, Werner T, Barlage S, Schmitz G. E-LDL and ox-LDL differentially regulate ceramide and cholesterol raft microdomains in human macrophages. Cytometry Part A 2006;69A:189-191.
Bhakdi S, Dorweiler B, Kirchmann R, Torzewski J, Weise E, Tranum-Jensen J, Walev I, Wieland E. On the pathogenesis of atherosclerosis: Enzymatic transformation of human low density lipoprotein to an atherogenic moiety. J Exp Med 1995;182:1959-1971.
Orsó E, Matysik S, Grandl M, Liebisch G, Schmitz G. Human native, enzymatically modified and oxidized low density lipoproteins show different lipidomic pattern. Biochim Biophys Acta 2015;1851:299-306.
Orsó E, Grandl M, Schmitz G. Oxidized LDL-induced endolysosomal phospholipidosis and enzymatically modified LDL-induced foam cell formation determine specific lipid species modulation in human macrophages. Chem Phys Lipids 2011;164:479-487.
Stöhr J, Schindler G, Rothe G, Schmitz G. Enhanced upregulation of the fc gamma receptor IIIa (CD16a) during in vitro differentiation of ApoE4/4 monocytes. Arterioscler Thromb Vasc Biol 1998;18:1424-1432.
Oswald S, Scheuch E, Cascorbi I, Siegmund W. A LC-MS/MS method to quantify the novel cholesterol lowering drug ezetimibe in human serum, urine and feces in healthy subjects genotyped for SLCO1B1. J Chromatogr B 2006;830:143-150.
Seedorf U, Engel T, Lueken A, Bode G, Lorkowski S, Assmann G. Cholesterol absorption inhibitor Ezetimibe blocks uptake of oxidized LDL in human macrophages. Biochem Biophys Res Commun 2004;320:1337-1341.
Labonté ED, Howles PN, Granholm NA, Rojas JC, Davies JP, Ioannou YA, Hui DY. Class B type I scavenger receptor is responsible for the high affinity cholesterol binding activity of intestinal brush border membrane vesicles. Biochim Biophys Acta 2007;1771:1132-1139.
Schweitzer M, Makhoul S, Paliouras M, Beitel LK, Gottlieb B, Trifiro M, Chowdhury SF, Zaman NM, Wang E, Davis H, et al. Characterization of the NPC1L1 gene and proteome from an exceptional responder to ezetimibe. Atherosclerosis 2016;246:78-86.
Oswald S, König J, Lütjohann D, Giessmann T, Kroemer HK, Rimmbach C, Rosskopf D, Fromm MF, Siegmund W. Disposition of ezetimibe is influenced by polymorphisms of the hepatic uptake carrier OATP1B1. Pharmacogenet Genomics 2008;18:559-568.
Andrade-Neto VV, Cunha-Júnior EF, Canto-Cavalheiro MM, Atella GC, Fernandes TA, Costa PR, Torres-Santos EC. Antileishmanial activity of ezetimibe: Inhibition of sterol biosynthesis, in vitro synergy with azoles, and efficacy in experimental cutaneous leishmaniasis. Antimicrob Agents Chemother 2016;60:6844-6852.
Suda H, Aoyagi T, Takeuchi T, Umezawa H. Inhibition of aminopeptidase B and leucine aminopeptidase by bestatin and its stereoisomers. Arch Biochem Biophys 1976;177:196-200.
Macintyre EA, Roberts PJ, Jones M, Van der Schoot CE, Favalaro EJ, Tidman N, Linch DC. Activation of humen monocytes occurs on cross-linking monocytic antigens to an fc receptor. J Immunol 1989;142:2377-2383.
Robenek H, Hofnagel O, Buers I, Robenek MJ, Troyer D, Severs NJ. Adipophilin-enriched domains in the ER membrane are sites of lipid droplet biogenesis. J Cell Sci 2006;119:4215-4224.
Fujimoto K. Freeze-fracture replica electron microscopy combined with SDS digestion for cytochemical labeling of integral membrane proteins. Application to the immunogold labeling of intercellular junctional complexes. J Cell Sci 1995;108:3443-3449.
Bared SM, Buechler C, Boettcher A, Dayoub R, Sigruener A, Grandl M, Rudolph C, Dada A, Schmitz G. Association of ABCA1 with syntaxin 13 and flotillin-1 and enhanced phagocytosis in tangier cells. Mol Biol Cell 2004;15:5399-5407.
Wolf Z, Orsó E, Werner T, Kluenemann HH, Schmitz G. Monocyte cholesterol homeostasis correlates with the presence of detergent resistant membrane microdomains. Cytometry Part A 2007;71A:486-494.
Pfeiffer A, Boettcher A, Orsó E, Kapinsky M, Nagy P, Bodnár A, Spreitzer I, Liebisch G, Drobnik W, Gempel K, et al. Lipopolysaccharide and ceramide docking to CD14 provokes ligand-specific receptor clustering in rafts. Eur J Immunol 2001;31:3153-3164.
Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 1959;37:911-917.
Liebisch G, Binder M, Schifferer R, Langmann T, Schulz B, Schmitz G. High throughput quantification of cholesterol and cholesteryl ester by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Biochim Biophys Acta 2006;1761:121-128.
Liebisch G, Lieser B, Rathenberg J, Drobnik W, Schmitz G. High-throughput quantification of phosphatidylcholine and sphingomyelin by electrospray ionization tandem mass spectrometry coupled with isotope correction algorithm. Biochim Biophys Acta 2004;1686:108-117.
Drobnik W, Borsukova H, Boettcher A, Pfeiffer A, Liebisch G, Schuetz GJ, Schindler H, Schmitz G. Apo AI/ABCA1-dependent and HDL3-mediated lipid efflux from compositionally distinct cholesterol-based microdomains. Traffic 2002;3:268-278.
Langmann T, Mauerer R, Zahn A, Moehle C, Probst M, Stremmel W, Schmitz G. Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues. Clin Chem 2003;49:230-238.
Riemann D, Tcherkes A, Hansen GH, Wulfaenger J, Blosz T, Danielsen EM. Functional co-localization of monocytic aminopeptidase N/CD13 with the fc gamma receptors CD32 and CD64. Biochem Biophys Res Commun 2005;331:1408-1412.
Navarrate Santos A, Roentsch J, Danielsen EM, Langner J, Riemann D. Aminopeptidase N/CD13 is associated with raft membrane microdomains in monocytes. Biochem Biophys Res Commun 2000;269:143-148.
Schmitz G, Langmann T. Transcriptional regulatory networks in lipid metabolism control ABCA1 expression. Biochim Biophys Acta 2005;1735:1-19.
Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, Tontonoz P. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 2000;97:12097-12102.
Suguro T, Takuya W, Kanome T, Kodate S, Hirano T, Miyazaki A, Adachi M. Serotonin acts as an up-regulator of acyl-coenzyme A:Cholesterol acyltransferase-1 in human monocyte-macrophages. Atherosclerosis 2006;186:278-281.
Kramer W, Girbig F, Corsiero D, Pfenninger A, Frick W, Jaehne G. Molecular elucidation of intestinal cholesterol absorption. In: Paumgartner G, Leuschner U, Keppler D, Stiehl A, editors. Bile Acid Biology and its Therapeuitc Implications. Dordrecht: Springer, 2005; p. 153-167.
Hui DY, Labonté ED, Howles PN. Development and physiological regulation of intestinal lipid absorption. III. Intestinal transporters and cholesterol absorption. Am J Physiol Gastrointest Liver Physiol 2008;294:G839-G843.
Knöpfel M, Davies JP, Duong PT, Kvaernø L, Carreira EM, Phillips MC, Ioannou YA, Hauser H. Multiple plasma membrane receptors but not NPC1L1 mediate high-affinity, ezetimibe-sensitive cholesterol uptake into the intestinal brush border membrane. Biochim Biophys Acta 2007;1771:1140-1147.
Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol Rev 2012;92:1061-1085.
Davies JP, Ioannou YA. The role of the Niemann-pick C1-like 1 protein in the subcellular transport of multiple lipids and their homeostasis. Curr Opin Lipidol 2006;17:221-226.
Orsó E, Werner T, Wolf Z, Bandulik S, Kramer W, Schmitz G. Ezetimib influences the expression of raft-associated antigens in human monocytes. Cytometry Part A 2006;69A:206-208.
Llaverias G, Laguna JC, Alegret M. Pharmacology of the ACAT inhibitor avasimibe (CI-1011). Cardiovasc Drug Rev 2003;21:33-50.
Schmitz G, Niemann R, Brennhausen B, Krause R, Assmann G. Regulation of high density lipoprotein receptors in cultured macrophages: Role of acyl-CoA:Cholesterol acyltransferase. EMBO J 1985;4:2773-2779.
Schmitz G, Robenek H, Beuck M, Krause R, Schurek A, Niemann R. Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism. Arteriosclerosis 1988;8:46-56.
Robenek H, Schmitz G. Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. II. Characterization of intracellular morphologic changes. Arteriosclerosis 1988;8:57-67.
Smart EJ, Ying Y, Donzell WC, Anderson RGW. A role for caveolin in transport of cholesterol from endoplasmic reticulum to plasma membrane. J Biol Chem 1996;271:29427-29435.
Kruth HS, Ifrim I, Chang J, Addadi L, Perl-Treves D, Zhang WY. Monoclonal antibody detection of plasma membrane cholesterol microdomains responsive to cholesterol trafficking. J Lipid Res 2001;42:1492-1500.
Liscum L, Munn NJ. Intracellular cholesterol transport. Biochem Biophys Acta 1999;1438:19-37.
Härmälä AS, Pörn MI, Slotte JP. Sphingosine inhibits sphingomyelinase-induced cholesteryl ester formation in cultured fibroblasts. Biochem Biophys Acta 1993;1210:97-104.
Slotte JP, Bierman EL. Depletion of plasma-membrane sphingomyelin rapidly alters the distribution of cholesterol between plasma membranes and intracellular cholesterol pools in cultured fibroblasts. Biochem J 1988;250:653-658.
Slotte JP, Tenhunen J, Pörn I. Effects of sphingomyelin degradation on cholesterol mobilization and efflux to high-density lipoproteins in cultured fibroblasts. Biochem Biophys Acta 1990;1025:152-156.
Zha X, Pierini LM, Leopold PL, Skiba PJ, Tabas I, Maxfield FR. Sphingomyelinase treatment induces ATP-independent endocytosis. J Cell Biol 1998;140:39-47.
Tabas I, Rosoff WJ, Boykow GC. Acyl coenzyme A:Cholesterol acyl transferase in macrophages utilizes a cellular pool of cholesterol oxidase-accessible cholesterol as substrate. J Biol Chem 1988;263:1266-1272.
Slotte JP. Enzyme-catalyzed oxidation of cholesterol in mixed phospholipid monolayers reveals the stoichiometry at which free cholesterol clusters disappear. Biochemistry 1992;31:5472-5477.
Pörn MI. Slotte JP. Reversible effects of sphingomyelin degradation on cholesterol distribution and metabolism in fibroblasts and transformed neuroblastoma cells. Biochem J 1990;271:121-126.
Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331-340.
Gong Y, Lee JN, Lee PCW, Goldstein JL, Brown MS, Ye J. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab 2006;3:15-24.
Engelking LJ, Liang G, Hammer RE, Takaishi K, Kuriyama H, Evers BM, Li WP, Horton JD, Goldstein JL, Brown MS. Schoenheimer effect explained-Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest 2005;115:2489-2498.
Blanchette-Mackie EJ. Intracellular cholesterol trafficking: Role of the NPC1 protein. Biochem Biophys Acta 2000;1486:171-183.
Sudhop T, von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002;62:2333-2347.