메뉴 건너뛰기




Volumn 30, Issue 3, 2012, Pages 489-503

Brain pericytes abca1 expression mediates cholesterol efflux but not cellular amyloid-β peptide accumulation

Author keywords

24S hydroxycholesterol; ABCA1; Alzheimer's disease; amyloid peptides; liver X receptors; pericytes

Indexed keywords

24 HYDROXYCHOLESTEROL; ABC TRANSPORTER A1; AMYLOID BETA PROTEIN; AMYLOID BETA PROTEIN[1-40]; AMYLOID BETA PROTEIN[1-42]; APOLIPOPROTEIN A1; APOLIPOPROTEIN E; CHOLESTEROL DERIVATIVE; UNCLASSIFIED DRUG;

EID: 84862878635     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-2012-112090     Document Type: Article
Times cited : (54)

References (62)
  • 1
    • 0037230328 scopus 로고    scopus 로고
    • Outsourcing in the brain: Do neurons depend on cholesterol delivery by astrocytes?
    • Pfrieger FW (2003) Outsourcing in the brain: Do neurons depend on cholesterol delivery by astrocytes? Bioessays 25, 72-78.
    • (2003) Bioessays , vol.25 , pp. 72-78
    • Pfrieger, F.W.1
  • 2
    • 2442557294 scopus 로고    scopus 로고
    • Brain cholesterol: Long secret life behind a barrier
    • Bjorkhem I, Meaney S (2004) Brain cholesterol: Long secret life behind a barrier. Arterioscler Thromb Vasc Biol 24, 806-815.
    • (2004) Arterioscler Thromb Vasc Biol , vol.24 , pp. 806-815
    • Bjorkhem, I.1    Meaney, S.2
  • 3
    • 0036916491 scopus 로고    scopus 로고
    • On the rate of translocatio in vitro and kinetics in vivo of the major oxysterols in human circulation: Critical importance of the position of the oxygen function
    • Meaney S, Bodin K, Diczfalusy U, Bjorkhem I (2002) On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: Critical importance of the position of the oxygen function. J Lipid Res 43, 2130-2135.
    • (2002) J Lipid Res , vol.43 , pp. 2130-2135
    • Meaney, S.1    Bodin, K.2    Diczfalusy, U.3    Bjorkhem, I.4
  • 4
    • 0029835410 scopus 로고    scopus 로고
    • Cholesterol homeostasis in human brain: Evidence for an age-dependent flux of 24Shydroxycholesterol from the brain into the circulation
    • Lutjohann D, Breuer O, Ahlborg G, Nennesmo I, Siden A, Diczfalusy U, Bjorkhem I (1996) Cholesterol homeostasis in human brain: Evidence for an age-dependent flux of 24Shydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 93, 9799-9804.
    • (1996) Proc Natl Acad Sci U S A , vol.93 , pp. 9799-9804
    • Lutjohann, D.1    Breuer, O.2    Ahlborg, G.3    Nennesmo, I.4    Siden, A.5    Diczfalusy, U.6    Bjorkhem, I.7
  • 5
    • 0031848338 scopus 로고    scopus 로고
    • Cholesterol homeostasis in human brain: Turnover of 24S- hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation
    • Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G,Wahren J (1998) Cholesterol homeostasis in human brain: Turnover of 24S- hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39, 1594-1600.
    • (1998) J Lipid Res , vol.39 , pp. 1594-1600
    • Bjorkhem, I.1    Lutjohann, D.2    Diczfalusy, U.3    Stahle, L.4    Ahlborg, G.5    Wahren, J.6
  • 6
    • 39749104095 scopus 로고    scopus 로고
    • Role of ATP-binding cassette transporters in brain lipid transport and neurological disease
    • Kim WS,Weickert CS, Garner B (2008) Role of ATP-binding cassette transporters in brain lipid transport and neurological disease. J Neurochem 104, 1145-1166.
    • (2008) J Neurochem , vol.104 , pp. 1145-1166
    • Kim, W.S.1    Weickert, C.S.2    Garner, B.3
  • 9
    • 33645237578 scopus 로고    scopus 로고
    • Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia
    • Karten B, Campenot RB, Vance DE, Vance JE (2006) Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia. J Biol Chem 281, 4049-4057.
    • (2006) J Biol Chem , vol.281 , pp. 4049-4057
    • Karten, B.1    Campenot, R.B.2    Vance, D.E.3    Vance, J.E.4
  • 11
    • 34047250984 scopus 로고    scopus 로고
    • Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein e discs and suppression of amyloidbeta peptide generation
    • Kim WS, Rahmanto AS, Kamili A, Rye KA, Guillemin GJ, Gelissen IC, Jessup W, Hill AF, Garner B (2007) Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloidbeta peptide generation. J Biol Chem 282, 2851-2861.
    • (2007) J Biol Chem , vol.282 , pp. 2851-2861
    • Kim, W.S.1    Rahmanto, A.S.2    Kamili, A.3    Rye, K.A.4    Guillemin, G.J.5    Gelissen, I.C.6    Jessup, W.7    Hill, A.F.8    Garner, B.9
  • 12
    • 34547582862 scopus 로고    scopus 로고
    • Regulation of central nervous system cholesterol homeostasis by the liver X receptor agonist TO-901317
    • Eckert GP, Vardanian L, Rebeck GW, Burns MP (2007) Regulation of central nervous system cholesterol homeostasis by the liver X receptor agonist TO-901317. Neurosci Lett 423, 47-52.
    • (2007) Neurosci Lett , vol.423 , pp. 47-52
    • Eckert, G.P.1    Vardanian, L.2    Rebeck, G.W.3    Burns, M.P.4
  • 13
    • 33846827336 scopus 로고    scopus 로고
    • 24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical-and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression
    • Fujiyoshi M, Ohtsuki S, Hori S, Tachikawa M, Terasaki T (2007) 24S-hydroxycholesterol induces cholesterol release from choroid plexus epithelial cells in an apical-and apoE isoform-dependent manner concomitantly with the induction of ABCA1 and ABCG1 expression. J Neurochem 100, 968-978.
    • (2007) J Neurochem , vol.100 , pp. 968-978
    • Fujiyoshi, M.1    Ohtsuki, S.2    Hori, S.3    Tachikawa, M.4    Terasaki, T.5
  • 14
  • 18
    • 77958594257 scopus 로고    scopus 로고
    • ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice
    • Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285, 34144-34154.
    • (2010) J Biol Chem , vol.285 , pp. 34144-34154
    • Donkin, J.J.1    Stukas, S.2    Hirsch-Reinshagen, V.3    Namjoshi, D.4    Wilkinson, A.5    May, S.6    Chan, J.7    Fan, J.8    Collins, J.9    Wellington, C.L.10
  • 19
    • 77952630395 scopus 로고    scopus 로고
    • Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice
    • Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, Lefterov I, Koldamova R (2010) Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci 30, 6862-6872.
    • (2010) J Neurosci , vol.30 , pp. 6862-6872
    • Fitz, N.F.1    Cronican, A.2    Pham, T.3    Fogg, A.4    Fauq, A.H.5    Chapman, R.6    Lefterov, I.7    Koldamova, R.8
  • 23
    • 81855168382 scopus 로고    scopus 로고
    • Processing of endogenous A-PP in blood-brain barrier endothelial cells is modulated by liver-x receptor agonists and altered cellular cholesterol homeostasis
    • Schweinzer C, Kober A, Lang I, Etschmaier K, Scholler M, Kresse A, Sattler W, Panzenboeck U (2011) Processing of endogenous A-PP in blood-brain barrier endothelial cells is modulated by liver-x receptor agonists and altered cellular cholesterol homeostasis. J Alzheimers Dis 27, 341-360.
    • (2011) J Alzheimers Dis , vol.27 , pp. 341-360
    • Schweinzer, C.1    Kober, A.2    Lang, I.3    Etschmaier, K.4    Scholler, M.5    Kresse, A.6    Sattler, W.7    Panzenboeck, U.8
  • 24
    • 38149090292 scopus 로고    scopus 로고
    • The blood-brain barrier in health and chronic neurodegenerative disorders
    • Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178-201.
    • (2008) Neuron , vol.57 , pp. 178-201
    • Zlokovic, B.V.1
  • 25
    • 78649487239 scopus 로고    scopus 로고
    • Pericytes are required for blood-brain barrier integrity during embryogenesis
    • Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562-566.
    • (2010) Nature , vol.468 , pp. 562-566
    • Daneman, R.1    Zhou, L.2    Kebede, A.A.3    Barres, B.A.4
  • 26
    • 79961230399 scopus 로고    scopus 로고
    • Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises
    • Armulik A, Genove G, Betsholtz C (2011) Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21, 193-215.
    • (2011) Dev Cell , vol.21 , pp. 193-215
    • Armulik, A.1    Genove, G.2    Betsholtz, C.3
  • 27
    • 58149131290 scopus 로고    scopus 로고
    • Transcriptional profiles of receptors and transporters involved in brain cholesterol homeostasis at the blood-brain barrier: Use of a in vitro model
    • Gosselet F, Candela P, Sevin E, Berezowski V, Cecchelli R, Fenart L (2009) Transcriptional profiles of receptors and transporters involved in brain cholesterol homeostasis at the blood-brain barrier: Use of an in vitro model. Brain Res 1249, 34-42.
    • (2009) Brain Res , vol.1249 , pp. 34-42
    • Gosselet, F.1    Candela, P.2    Sevin, E.3    Berezowski, V.4    Cecchelli, R.5    Fenart, L.6
  • 28
    • 0037044840 scopus 로고    scopus 로고
    • ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at a in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells
    • Panzenboeck U, Balazs Z, Sovic A, Hrzenjak A, Levak-Frank S, Wintersperger A, Malle E, Sattler W (2002) ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem 277, 42781-42789.
    • (2002) J Biol Chem , vol.277 , pp. 42781-42789
    • Panzenboeck, U.1    Balazs, Z.2    Sovic, A.3    Hrzenjak, A.4    Levak-Frank, S.5    Wintersperger, A.6    Malle, E.7    Sattler, W.8
  • 29
    • 33646205692 scopus 로고    scopus 로고
    • Regulatory effects of synthetic liver X receptor-and peroxisomeproliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells
    • Panzenboeck U, Kratzer I, Sovic A, Wintersperger A, Bernhart E, Hammer A, Malle E, Sattler W (2006) Regulatory effects of synthetic liver X receptor-and peroxisomeproliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells. Int J Biochem Cell Biol 38, 1314-1329.
    • (2006) Int J Biochem Cell Biol , vol.38 , pp. 1314-1329
    • Panzenboeck, U.1    Kratzer, I.2    Sovic, A.3    Wintersperger, A.4    Bernhart, E.5    Hammer, A.6    Malle, E.7    Sattler, W.8
  • 30
    • 38349098471 scopus 로고    scopus 로고
    • Expression of nuclear receptor mRNA and liver X receptor-mediated regulation of ABC transporter A1 at rat blood-brain barrier
    • Akanuma S, Hori S, Ohtsuki S, Fujiyoshi M, Terasaki T (2008) Expression of nuclear receptor mRNA and liver X receptor-mediated regulation of ABC transporter A1 at rat blood-brain barrier. Neurochem Int 52, 669-674.
    • (2008) Neurochem Int , vol.52 , pp. 669-674
    • Akanuma, S.1    Hori, S.2    Ohtsuki, S.3    Fujiyoshi, M.4    Terasaki, T.5
  • 31
    • 78650659385 scopus 로고    scopus 로고
    • Apicalto-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by Pglycoprotein
    • Candela P, Gosselet F, Saint-Pol J, Sevin E, Boucau MC, Boulanger E, Cecchelli R, Fenart L (2010) Apicalto-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by Pglycoprotein. J Alzheimers Dis 22, 849-859.
    • (2010) J Alzheimers Dis , vol.22 , pp. 849-859
    • Candela, P.1    Gosselet, F.2    Saint-Pol, J.3    Sevin, E.4    Boucau, M.C.5    Boulanger, E.6    Cecchelli, R.7    Fenart, L.8
  • 35
    • 1642277686 scopus 로고    scopus 로고
    • Depletion of pre-beta-high density lipoprotein by human chymase impairs ATP-binding cassette transporter A1-but not scavenger receptor class B type I-mediated lipid efflux to high density lipoprotein
    • Favari E, Lee M, Calabresi L, Franceschini G, Zimetti F, Bernini F, Kovanen PT (2004) Depletion of pre-beta-high density lipoprotein by human chymase impairs ATP-binding cassette transporter A1-but not scavenger receptor class B type I-mediated lipid efflux to high density lipoprotein. J Biol Chem 279, 9930-9936.
    • (2004) J Biol Chem , vol.279 , pp. 9930-9936
    • Favari, E.1    Lee, M.2    Calabresi, L.3    Franceschini, G.4    Zimetti, F.5    Bernini, F.6    Kovanen, P.T.7
  • 37
    • 8144228674 scopus 로고    scopus 로고
    • Cellular physiology of cholesterol efflux in vascular endothelial cells
    • O'Connell BJ, Denis M, Genest J (2004) Cellular physiology of cholesterol efflux in vascular endothelial cells. Circulation 110, 2881-2888.
    • (2004) Circulation , vol.110 , pp. 2881-2888
    • O'connell, B.J.1    Denis, M.2    Genest, J.3
  • 38
    • 40949149021 scopus 로고    scopus 로고
    • ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier
    • Akanuma S, Ohtsuki S, Doi Y, Tachikawa M, Ito S, Hori S, Asashima T, Hashimoto T, Yamada K, Ueda K, Iwatsubo T, Terasaki T (2008) ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier. Neurochem Int 52, 956-961.
    • (2008) Neurochem Int , vol.52 , pp. 956-961
    • Akanuma, S.1    Ohtsuki, S.2    Doi, Y.3    Tachikawa, M.4    Ito, S.5    Hori, S.6    Asashima, T.7    Hashimoto, T.8    Yamada, K.9    Ueda, K.10    Iwatsubo, T.11    Terasaki, T.12
  • 39
    • 78449232720 scopus 로고    scopus 로고
    • Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice
    • Lefterov I, Fitz NF, Cronican AA, Fogg A, Lefterov P, Kodali R, Wetzel R, Koldamova R (2010) Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. J Biol Chem 285, 36945-36957.
    • (2010) J Biol Chem , vol.285 , pp. 36945-36957
    • Lefterov, I.1    Fitz, N.F.2    Cronican, A.A.3    Fogg, A.4    Lefterov, P.5    Kodali, R.6    Wetzel, R.7    Koldamova, R.8
  • 41
    • 0031017399 scopus 로고    scopus 로고
    • Rapid degeneration of cultured human brain pericytes by amyloid beta protein
    • Verbeek MM, de Waal RM, Schipper JJ, Van Nostrand WE (1997) Rapid degeneration of cultured human brain pericytes by amyloid beta protein. J Neurochem 68, 1135-1141.
    • (1997) J Neurochem , vol.68 , pp. 1135-1141
    • Verbeek, M.M.1    De Waal, R.M.2    Schipper, J.J.3    Van Nostrand, W.E.4
  • 42
    • 3242682550 scopus 로고    scopus 로고
    • Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistanceassociated proteins in a in vitro model of the blood-brain barrier
    • Berezowski V, Landry C, Dehouck MP, Cecchelli R, Fenart L (2004) Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistanceassociated proteins in an in vitro model of the blood-brain barrier. Brain Res 1018, 1-9.
    • (2004) Brain Res , vol.1018 , pp. 1-9
    • Berezowski, V.1    Landry, C.2    Dehouck, M.P.3    Cecchelli, R.4    Fenart, L.5
  • 43
    • 33751096969 scopus 로고    scopus 로고
    • Crossing the barrier: Oxysterols as cholesterol transporters and metabolic modulators in the brain
    • Bjorkhem I (2006) Crossing the barrier: Oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 260, 493-508.
    • (2006) J Intern Med , vol.260 , pp. 493-508
    • Bjorkhem, I.1
  • 45
    • 3142709408 scopus 로고    scopus 로고
    • Probucol inactivatesABCA1in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation
    • Wu CA, Tsujita M, Hayashi M, Yokoyama S (2004) Probucol inactivatesABCA1in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation. J Biol Chem 279, 30168-30174.
    • (2004) J Biol Chem , vol.279 , pp. 30168-30174
    • Wu, C.A.1    Tsujita, M.2    Hayashi, M.3    Yokoyama, S.4
  • 46
    • 38849122775 scopus 로고    scopus 로고
    • Liver X receptors (LXRs). Part I: Structure, function, regulation of activity, and role in lipid metabolism
    • Wojcicka G, Jamroz-Wisniewska A, Horoszewicz K, Beltowski J (2007) Liver X receptors (LXRs). Part I: Structure, function, regulation of activity, and role in lipid metabolism. Postepy Hig Med Dosw (Online) 61, 736-759.
    • (2007) Postepy Hig Med Dosw (Online) , vol.61 , pp. 736-759
    • Wojcicka, G.1    Jamroz-Wisniewska, A.2    Horoszewicz, K.3    Beltowski, J.4
  • 47
    • 38549141572 scopus 로고    scopus 로고
    • Cellular cholesterol trafficking and compartmentalization
    • Ikonen E (2008) Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol 9, 125-138.
    • (2008) Nat Rev Mol Cell Biol , vol.9 , pp. 125-138
    • Ikonen, E.1
  • 49
    • 0033968648 scopus 로고    scopus 로고
    • Apolipoprotein e exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture
    • Michikawa M, Fan QW, Isobe I, Yanagisawa K (2000) Apolipoprotein E exhibits isoform-specific promotion of lipid efflux from astrocytes and neurons in culture. J Neurochem 74, 1008-1016.
    • (2000) J Neurochem , vol.74 , pp. 1008-1016
    • Michikawa, M.1    Fan, Q.W.2    Isobe, I.3    Yanagisawa, K.4
  • 54
    • 74149083432 scopus 로고    scopus 로고
    • Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease
    • Hudry E,Van Dam D,KulikW, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P, Cartier N (2010) Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer's disease. Mol Ther 18, 44-53.
    • (2010) Mol Ther , vol.18 , pp. 44-53
    • Hudry, E.1    Van Dam, D.2    Kulik, W.3    De Deyn, P.P.4    Stet, F.S.5    Ahouansou, O.6    Benraiss, A.7    Delacourte, A.8    Bougneres, P.9    Aubourg, P.10    Cartier, N.11
  • 57
    • 30044438463 scopus 로고    scopus 로고
    • Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice
    • Koldamova R, Staufenbiel M, Lefterov I (2005) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280, 43224-43235.
    • (2005) J Biol Chem , vol.280 , pp. 43224-43235
    • Koldamova, R.1    Staufenbiel, M.2    Lefterov, I.3
  • 59
    • 77953258151 scopus 로고    scopus 로고
    • The role of ATPbinding cassette transporter A1 in Alzheimer's disease and neurodegeneration
    • Koldamova R, Fitz NF, Lefterov I (2010) The role of ATPbinding cassette transporter A1 in Alzheimer's disease and neurodegeneration. Biochim Biophys Acta 1801, 824-830.
    • (2010) Biochim Biophys Acta , vol.1801 , pp. 824-830
    • Koldamova, R.1    Fitz, N.F.2    Lefterov, I.3
  • 60
  • 62
    • 80052965098 scopus 로고    scopus 로고
    • Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target gene In Vivo
    • Shafaati M, Olin M, Bavner A, Pettersson H, Rozell B, Meaney S, Parini P, Bjorkhem I (2011) Enhanced production of 24S-hydroxycholesterol is not sufficient to drive liver X receptor target genes in vivo. J Intern Med 270, 377-387.
    • (2011) J Intern Med , vol.270 , pp. 377-387
    • Shafaati, M.1    Olin, M.2    Bavner, A.3    Pettersson, H.4    Rozell, B.5    Meaney, S.6    Parini, P.7    Bjorkhem, I.8


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.