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Kerryanne Rye - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein A i improves pAncreAtic β cell function independent of the Atp binding cAssette trAnsporters AbcA1 And Abcg1
The FASEB Journal, 2019Co-Authors: Liming Hou, Shudi Tang, Kwok Leung Ong, Marit Westerterp, Philip J Barter, Blake J Cochran, Fatiha Tabet, Kerryanne RyeAbstract:Apolipoprotein A-I (ApoA-I), the mAin protein constituent of HDLs, increAses insulin synthesis And insulin secretion in pAncreAtic β cells. ApoA-I Also Accepts cholesterol thAt effluxes from cells expressing ATP-binding cAssette trAnsporter A1 (ABCA1) And ATP-binding cAssette trAnsporter G1 (ABCG1). Mice with conditionAl deletion of ABCA1 And ABCG1 in β cells [β-double knockout (DKO) mice] hAve increAsed islet cholesterol levels And reduced glucose-stimulAted insulin secretion (GSIS). The project Asks whether metAbolic pAthwAys Are dysregulAted in β-DKO mouse islets And whether this cAn be corrected, And GSIS improved, by treAtment with ApoA-I. β-DKO mice were treAted with ApoA-I or PBS, And islets were isolAted for determinAtion of GSIS. TotAl RNA wAs extrActed from β-DKO And control mouse islets for microArrAy AnAlysis. MetAbolic pAthwAys were interrogAted by functionAl enrichment AnAlysis. ApoA-I treAtment improved GSIS in β-DKO but not control mouse islets. PlAsmA lipid And lipoprotein levels And islet cholesterol levels were Also unAffected by treAtment with ApoA-I. Cholesterol metAbolism, glucose metAbolism, And inflAmmAtion pAthwAys were dysregulAted in β-DKO mouse islets. This wAs not corrected by treAtment with ApoA-I. In summAry, ApoA-I treAtment improves GSIS by A cholesterol-independent mechAnism, but it does not correct metAbolic dysregulAtion in β-DKO mouse islets.-Hou, L., TAng, S., Wu, B. J., Ong, K.-L., Westerterp, M., BArter, P. J., CochrAn, B. J., TAbet, F., Rye, K.-A. Apolipoprotein A-I improves pAncreAtic β-cell function independent of the ATP-binding cAssette trAnsporters ABCA1 And ABCG1.
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humAn mAcrophAge cAthepsin b mediAted c terminAl cleAvAge of Apolipoprotein A i At ser228 severely impAirs AntiAtherogenic cApAcity
The FASEB Journal, 2016Co-Authors: Donna Lee M Dinnes, Liming Hou, Kerryanne Rye, Melanie Y White, Maaike Kockx, Mathew Traini, Victar Hsieh, Mijurng Kim, Wendy Jessup, Morten ThaysenandersenAbstract:Apolipoprotein A-I (ApoA-I) is the mAjor component of HDL And centrAl to the Ability of HDL to stimulAte ATP-binding cAssette trAnsporter A1 (ABCA1)-dependent, AntiAtherogenic export of cholesterol from mAcrophAge foAm cells, A key plAyer in the pAthology of Atherosclerosis. Cell-mediAted modificAtions of ApoA-I, such As chlorinAtion, nitrAtion, oxidAtion, And proteolysis, cAn impAir its AntiAtherogenic function, Although it is unknown whether mAcrophAges themselves contribute to such modificAtions. To investigAte this, humAn monocyte-derived mAcrophAges (HMDMs) were incubAted with humAn ApoA-I under conditions used to induce cholesterol export. Two-dimensionAl gel electrophoresis And Western blot AnAlysis identified thAt ApoA-I is cleAved (∼20-80%) by HMDMs in A time-dependent mAnner, generAting ApoA-I of lower MW And isoelectric point. MAss spectrometry AnAlysis identified A novel C-terminAl cleAvAge site of ApoA-I between Ser228-Phe229 RecombinAnt ApoA-I truncAted At Ser228 demonstrAted profound loss of cApAcity to solubilize lipid And to promote ABCA1-dependent cholesterol efflux. ProteAse inhibitors, smAll interfering RNA knockdown in HMDMs, mAss spectrometry AnAlysis, And cAthepsin B Activity AssAys identified secreted cAthepsin B As responsible for ApoA-I cleAvAge At Ser228 ImportAntly, C-terminAl cleAvAge of ApoA-I wAs Also detected in humAn cArotid plAque. CleAvAge At Ser228 is A novel, functionAlly importAnt post-trAnslAtionAl modificAtion of ApoA-I mediAted by HMDMs thAt limits the AntiAtherogenic properties of ApoA-I.-Dinnes, D. L. M., White, M. Y., Kockx, M., TrAini, M., Hsieh, V., Kim, M.-J., Hou, L., Jessup, W., Rye, K.-A., ThAysen-Andersen, M., Cordwell, S. J., KrithArides, L. HumAn mAcrophAge cAthepsin B-mediAted C-terminAl cleAvAge of Apolipoprotein A-I At Ser228 severely impAirs AntiAtherogenic cApAcity.
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inhibition of Arthritis in the lewis rAt by Apolipoprotein A i And reconstituted high density lipoproteins
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Kwok L Ong, Philip J Barter, Fatiha Tabet, Sudichhya Shrestha, Kang Chen, Kerryanne RyeAbstract:Objective— This study questions whether high-density lipoproteins (HDLs) And Apolipoprotein A-I inhibit joint inflAmmAtion in streptococcAl cell wAll peptidoglycAn-polysAcchAride (PG-PS)–induced Arthritis in femAle Lewis rAts. ApproAch And Results— AdministrAtion of PG-PS to femAle Lewis rAts cAused Acute joint inflAmmAtion After 4 dAys, followed by remission by dAy 8. The AnimAls subsequently developed chronic joint inflAmmAtion thAt persisted until euthAnAsiA At dAy 21. TreAtment with Apolipoprotein A-I 24 hours before And 24 hours After PG-PS AdministrAtion reduced the Acute And chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I At dAys 7, 9, And 11 After PG-PS AdministrAtion reduced the chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I or reconstituted HDLs consisting of Apolipoprotein A-I complexed with phosphAtidylcholine 24 hours before And At dAys 1, 7, 9, And 11 After PG-PS AdministrAtion reduced Acute And chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I Also reduced the inflAmmAtory white blood cell count, synoviAl fluid proinflAmmAtory cytokine levels, synoviAl tissue mAcrophAge AccumulAtion, As well As toll-like receptor 2, And inflAmmAtory cytokine expression. At the moleculAr level, preincubAtion of humAn monocyte–derived mAcrophAges with Apolipoprotein A-I or reconstituted HDLs before PG-PS stimulAtion inhibited the PG-PS–induced increAse in toll-like receptor 2 And myeloid differentiAtion primAry response gene (88) mRNA levels, nucleAr fActor-κB ActivAtion, And proinflAmmAtory cytokine production. The effects of Apolipoprotein A-I And reconstituted HDLs were Abolished by trAnsfecting the humAn monocyte–derived mAcrophAges with ATP-binding cAssette trAnsporter A1 or G1 siRNA. Conclusions— Apolipoprotein A-I And reconstituted HDLs AttenuAte PG-PS–induced Arthritis in the rAt. Studies in humAn monocyte–derived mAcrophAges indicAte thAt this benefit mAy be becAuse of the inhibition of toll-like receptor 2 expression And decreAsed nucleAr fActor-κB ActivAtion in mAcrophAges.
Jay W Heinecke - One of the best experts on this subject based on the ideXlab platform.
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tertiAry structure of Apolipoprotein A i in nAscent high density lipoproteins
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Mohsen Pourmousa, Jere P Segrest, Hyun Deok Song, Yi He, Jay W Heinecke, Richard W PastorAbstract:UnderstAnding the function of high-density lipoprotein (HDL) requires detAiled knowledge of the structure of its primAry protein, Apolipoprotein A-I (APOA1). However, APOA1 flexibility And HDL heterogeneity hAve confounded decAdes of efforts to determine high-resolution structures And consistent models. Here, moleculAr dynAmics simulAtions totAling 30 μs on two nAscent HDLs, eAch with 2 APOA1 And either 160 phospholipids And 24 cholesterols or 200 phospholipids And 20 cholesterols, show thAt residues 1–21 of the N-terminAl domAins of APOA1 interAct viA strong sAlt bridges. Residues 26–43 of one APOA1 in the smAller pArticle form A hinge on the disc edge, which displAces the C-terminAl domAin of the other APOA1 to the phospholipid surfAce. The proposed structures Are supported by chemicAl cross-linking, RosettA modeling of the N-terminAl domAin, And AnAlysis of the lipid-free ∆185APOA1 crystAl structure. These structures provide A frAmework for understAnding HDL mAturAtion And revise All previous models of nAscent HDL.
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methionine oxidAtion impAirs reverse cholesterol trAnsport by Apolipoprotein A i
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Baohai Shao, Michael N Oda, Giorgio Cavigiolio, Nathan Brot, Jay W HeineckeAbstract:HDL protects AgAinst vAsculAr diseAse by Accepting free cholesterol from mAcrophAge foAm cells in the Artery wAll. This pAthwAy is criticAlly dependent on lecithin:cholesterol AcyltrAnsferAse (LCAT), which rApidly converts cholesterol to cholesteryl ester. The physiologicAl ActivAtor of LCAT is Apolipoprotein A-I (ApoA-I), the mAjor HDL protein. However, cholesterol removAl is compromised if ApoA-I is exposed to reActive intermediAtes. In humAns with estAblished cArdiovAsculAr diseAse, myeloperoxidAse (MPO) oxidizes HDL, And oxidAtion by MPO impAirs ApoA-I's Ability to ActivAte LCAT in vitro. BecAuse A single methionine residue in ApoA-I, Met-148, resides neAr the center of the protein's LCAT ActivAtion domAin, we determined whether its oxidAtion by MPO could Account for the loss of LCAT Activity. MAss spectrometric AnAlysis demonstrAted thAt oxidAtion of Met-148 to methionine sulfoxide AssociAted quAntitAtively with loss of LCAT Activity in both discoidAl HDL And HDL(3), the enzyme's physiologicAl substrAtes. Reversing oxidAtion with methionine sulfoxide reductAse restored HDL's Ability to ActivAte LCAT. DiscoidAl HDL prepAred with ApoA-I contAining A Met-148-->Leu mutAtion wAs significAntly resistAnt to inActivAtion by MPO. BAsed on structurAl dAtA in the literAture, we propose thAt oxidAtion of Met-148 disrupts ApoA-I's centrAl loop, which overlAps the LCAT ActivAtion domAin. These observAtions implicAte oxidAtion of A single Met in ApoA-I in impAired LCAT ActivAtion, A criticAl eArly step in reverse cholesterol trAnsport.
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methionine oxidAtion impAirs reverse cholesterol trAnsport by Apolipoprotein A i
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Baohai Shao, Giorgio Cavigiolio, Nathan Brot, Jay W HeineckeAbstract:AbstrAct HDL protects AgAinst vAsculAr diseAse by Accepting free cholesterol from mAcrophAge foAm cells in the Artery wAll. This pAthwAy is criticAlly dependent on lecithin:cholesterol AcyltrAnsferAse (LCAT), which rApidly converts cholesterol to cholesteryl ester. The physiologicAl ActivAtor of LCAT is Apolipoprotein A-I (ApoA-I), the mAjor HDL protein. However, cholesterol removAl is compromised if ApoA-I is exposed to reActive intermediAtes. In humAns with estAblished cArdiovAsculAr diseAse, myeloperoxidAse (MPO) oxidizes HDL, And oxidAtion by MPO impAirs ApoA-I's Ability to ActivAte LCAT in vitro. BecAuse A single methionine residue in ApoA-I, Met-148, resides neAr the center of the protein's LCAT ActivAtion domAin, we determined whether its oxidAtion by MPO could Account for the loss of LCAT Activity. MAss spectrometric AnAlysis demonstrAted thAt oxidAtion of Met-148 to methionine sulfoxide AssociAted quAntitAtively with loss of LCAT Activity in both discoidAl HDL And HDL3, the enzyme's physiologicAl substrAtes. Reversing oxidAtion with methionine sulfoxide reductAse restored HDL's Ability to ActivAte LCAT. DiscoidAl HDL prepAred with ApoA-I contAining A Met-148→Leu mutAtion wAs significAntly resistAnt to inActivAtion by MPO. BAsed on structurAl dAtA in the literAture, we propose thAt oxidAtion of Met-148 disrupts ApoA-I's centrAl loop, which overlAps the LCAT ActivAtion domAin. These observAtions implicAte oxidAtion of A single Met in ApoA-I in impAired LCAT ActivAtion, A criticAl eArly step in reverse cholesterol trAnsport. Atherosclerosis dysfunctionAl HDL hypochlorous Acid inflAmmAtion methionine sulfoxide reductAse
Trudy M Forte - One of the best experts on this subject based on the ideXlab platform.
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intrAvenous injection of Apolipoprotein A v reconstituted high density lipoprotein decreAses hypertriglyceridemiA in ApoAv mice And requires glycosylphosphAtidylinositol Anchored high density lipoprotein binding protein 1
Arteriosclerosis Thrombosis and Vascular Biology, 2010Co-Authors: Xiao Shu, Robert O Ryan, Lisa Nelbach, Michael M Weinstein, Braydon L Burgess, Jennifer A Beckstead, Stephen G Young, Trudy M ForteAbstract:Objective—Apolipoprotein A-V (ApoA-V), A minor protein AssociAted with lipoproteins, hAs A mAjor effect on triAcylglycerol (TG) metAbolism. We investigAted whether ApoA-V complexed with phospholipi...
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the c terminAl domAin of Apolipoprotein A i contAins A lipid sensitive conformAtionAl trigger
Nature Structural & Molecular Biology, 2003Co-Authors: Michael N Oda, Trudy M Forte, Robert O Ryan, John C VossAbstract:ExchAngeAble Apolipoproteins cAn convert between lipid-free And lipid-AssociAted stAtes. The C-terminAl domAin of humAn Apolipoprotein A-I (ApoA-I) plAys A role in both lipid binding And self-AssociAtion. Site-directed spin-lAbel electron pArAmAgnetic resonAnce spectroscopy wAs used to exAmine the structure of the ApoA-I C terminus in lipid-free And lipid-AssociAted stAtes. Nitroxide spin-lAbels positioned At defined locAtions throughout the C terminus were used to define discrete secondAry structurAl elements. MAgnetic interActions between probes locAlized At positions 163, 217 And 226 in singly And doubly lAbeled ApoA-I gAve inter- And intrAmoleculAr distAnce informAtion, providing A bAsis for mApping ApoA-I tertiAry And quAternAry structure. SpectrA of ApoA-I in reconstituted HDL reveAled A lipid-induced trAnsition of defined rAndom coils And betA-strAnds into AlphA-helices. This conformAtionAl switch is AnAlogous to triggered events in virAl fusion proteins And mAy serve As A meAns to overcome the energy bArriers of lipid sequestrAtion, A criticAl step in cholesterol efflux And HDL Assembly.
Anders G Olsson - One of the best experts on this subject based on the ideXlab platform.
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high density lipoprotein cholesterol high density lipoprotein pArticle size And Apolipoprotein A i significAnce for cArdiovAsculAr risk the ideAl And epic norfolk studies
Journal of the American College of Cardiology, 2008Co-Authors: Wim A Van Der Steeg, Erik S.g. Stroes, Ingar Holme, Matthijs S Boekholdt, Mogens Lytken Larsen, Christina Lindahl, Matti J Tikkanen, Nicholas J Wareham, Ole Faergeman, Anders G OlssonAbstract:Objectives: This study wAs designed to Assess the relAtionship of high-density-lipoprotein cholesterol (HDL-C), HDL pArticle size, And Apolipoprotein A-I (ApoA-I) with the occurrence of coronAry Ar ...
Philip J Barter - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein A i improves pAncreAtic β cell function independent of the Atp binding cAssette trAnsporters AbcA1 And Abcg1
The FASEB Journal, 2019Co-Authors: Liming Hou, Shudi Tang, Kwok Leung Ong, Marit Westerterp, Philip J Barter, Blake J Cochran, Fatiha Tabet, Kerryanne RyeAbstract:Apolipoprotein A-I (ApoA-I), the mAin protein constituent of HDLs, increAses insulin synthesis And insulin secretion in pAncreAtic β cells. ApoA-I Also Accepts cholesterol thAt effluxes from cells expressing ATP-binding cAssette trAnsporter A1 (ABCA1) And ATP-binding cAssette trAnsporter G1 (ABCG1). Mice with conditionAl deletion of ABCA1 And ABCG1 in β cells [β-double knockout (DKO) mice] hAve increAsed islet cholesterol levels And reduced glucose-stimulAted insulin secretion (GSIS). The project Asks whether metAbolic pAthwAys Are dysregulAted in β-DKO mouse islets And whether this cAn be corrected, And GSIS improved, by treAtment with ApoA-I. β-DKO mice were treAted with ApoA-I or PBS, And islets were isolAted for determinAtion of GSIS. TotAl RNA wAs extrActed from β-DKO And control mouse islets for microArrAy AnAlysis. MetAbolic pAthwAys were interrogAted by functionAl enrichment AnAlysis. ApoA-I treAtment improved GSIS in β-DKO but not control mouse islets. PlAsmA lipid And lipoprotein levels And islet cholesterol levels were Also unAffected by treAtment with ApoA-I. Cholesterol metAbolism, glucose metAbolism, And inflAmmAtion pAthwAys were dysregulAted in β-DKO mouse islets. This wAs not corrected by treAtment with ApoA-I. In summAry, ApoA-I treAtment improves GSIS by A cholesterol-independent mechAnism, but it does not correct metAbolic dysregulAtion in β-DKO mouse islets.-Hou, L., TAng, S., Wu, B. J., Ong, K.-L., Westerterp, M., BArter, P. J., CochrAn, B. J., TAbet, F., Rye, K.-A. Apolipoprotein A-I improves pAncreAtic β-cell function independent of the ATP-binding cAssette trAnsporters ABCA1 And ABCG1.
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inhibition of Arthritis in the lewis rAt by Apolipoprotein A i And reconstituted high density lipoproteins
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Kwok L Ong, Philip J Barter, Fatiha Tabet, Sudichhya Shrestha, Kang Chen, Kerryanne RyeAbstract:Objective— This study questions whether high-density lipoproteins (HDLs) And Apolipoprotein A-I inhibit joint inflAmmAtion in streptococcAl cell wAll peptidoglycAn-polysAcchAride (PG-PS)–induced Arthritis in femAle Lewis rAts. ApproAch And Results— AdministrAtion of PG-PS to femAle Lewis rAts cAused Acute joint inflAmmAtion After 4 dAys, followed by remission by dAy 8. The AnimAls subsequently developed chronic joint inflAmmAtion thAt persisted until euthAnAsiA At dAy 21. TreAtment with Apolipoprotein A-I 24 hours before And 24 hours After PG-PS AdministrAtion reduced the Acute And chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I At dAys 7, 9, And 11 After PG-PS AdministrAtion reduced the chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I or reconstituted HDLs consisting of Apolipoprotein A-I complexed with phosphAtidylcholine 24 hours before And At dAys 1, 7, 9, And 11 After PG-PS AdministrAtion reduced Acute And chronic joint inflAmmAtion. TreAtment with Apolipoprotein A-I Also reduced the inflAmmAtory white blood cell count, synoviAl fluid proinflAmmAtory cytokine levels, synoviAl tissue mAcrophAge AccumulAtion, As well As toll-like receptor 2, And inflAmmAtory cytokine expression. At the moleculAr level, preincubAtion of humAn monocyte–derived mAcrophAges with Apolipoprotein A-I or reconstituted HDLs before PG-PS stimulAtion inhibited the PG-PS–induced increAse in toll-like receptor 2 And myeloid differentiAtion primAry response gene (88) mRNA levels, nucleAr fActor-κB ActivAtion, And proinflAmmAtory cytokine production. The effects of Apolipoprotein A-I And reconstituted HDLs were Abolished by trAnsfecting the humAn monocyte–derived mAcrophAges with ATP-binding cAssette trAnsporter A1 or G1 siRNA. Conclusions— Apolipoprotein A-I And reconstituted HDLs AttenuAte PG-PS–induced Arthritis in the rAt. Studies in humAn monocyte–derived mAcrophAges indicAte thAt this benefit mAy be becAuse of the inhibition of toll-like receptor 2 expression And decreAsed nucleAr fActor-κB ActivAtion in mAcrophAges.
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the impAct of glycAtion on Apolipoprotein A i structure And its Ability to ActivAte lecithin cholesterol AcyltrAnsferAse
Diabetologia, 2007Co-Authors: E Nobecourt, Michael J Davies, Bronwyn E Brown, Linda K Curtiss, David J Bonnet, Francesca Charlton, Andrzej S Januszewski, Alicia J Jenkins, Philip J BarterAbstract:Aims/hypothesis HyperglycAemiA, one of the mAin feAtures of diAbetes, results in non-enzymAtic glycAtion of plAsmA proteins, including Apolipoprotein A-I (ApoA-I), the most AbundAnt Apolipoprotein in HDL. The Aim of this study wAs to determine how glycAtion Affects the structure of ApoA-I And its Ability to ActivAte lecithin:cholesterol AcyltrAnsferAse (LCAT), A key enzyme in reverse cholesterol trAnsport.