메뉴 건너뛰기




Volumn 62, Issue 4, 2013, Pages 1245-1257

Increase of palmitic acid concentration impairs endothelial progenitor cell and bone marrow-derived progenitor cell bioavailability: Role of the STAT5/PPARγ transcriptional complex

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN D1; CYCLINE; OLEIC ACID; PALMITIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; SMALL INTERFERING RNA; STAT5 PROTEIN; STEARIC ACID;

EID: 84875470405     PISSN: 00121797     EISSN: 1939327X     Source Type: Journal    
DOI: 10.2337/db12-0646     Document Type: Article
Times cited : (37)

References (50)
  • 1
    • 58249138618 scopus 로고    scopus 로고
    • Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry for metabonomics: Biomarker discovery for diabetes mellitus
    • Li X, Xu Z, Lu X, et al. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry for metabonomics: Biomarker discovery for diabetes mellitus. Anal Chim Acta 2009;633:257-262
    • (2009) Anal Chim Acta , vol.633 , pp. 257-262
    • Li, X.1    Xu, Z.2    Lu, X.3
  • 2
    • 84869031541 scopus 로고    scopus 로고
    • Metabolomics in diabetes research
    • Friedrich N. Metabolomics in diabetes research. J Endocrinol 2012;215: 29-42
    • (2012) J Endocrinol , vol.215 , pp. 29-42
    • Friedrich, N.1
  • 3
    • 77957319626 scopus 로고    scopus 로고
    • Free fatty acid metabolic profile and biomarkers of isolated post-challenge diabetes and type 2 diabetes mellitus based on GC-MS and multivariate statistical analysis
    • Liu L, Li Y, Guan C, et al. Free fatty acid metabolic profile and biomarkers of isolated post-challenge diabetes and type 2 diabetes mellitus based on GC-MS and multivariate statistical analysis. J Chromatogr B Analyt Technol Biomed Life Sci 2010;878:2817-2825
    • (2010) J Chromatogr B Analyt Technol Biomed Life Sci , vol.878 , pp. 2817-2825
    • Liu, L.1    Li, Y.2    Guan, C.3
  • 4
    • 0033009862 scopus 로고    scopus 로고
    • Free fatty acids, insulin resistance, and type 2 diabetes mellitus
    • Boden G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 1999;111:241-248
    • (1999) Proc Assoc Am Physicians , vol.111 , pp. 241-248
    • Boden, G.1
  • 5
    • 33845440474 scopus 로고    scopus 로고
    • Plasma fatty acid metabolic profiling and biomarkers of type 2 diabetes mellitus based on GC/MS and PLS-LDA
    • Yi LZ, He J, Liang YZ, Yuan DL, Chau FT. Plasma fatty acid metabolic profiling and biomarkers of type 2 diabetes mellitus based on GC/MS and PLS-LDA. FEBS Lett 2006;580:6837-6845
    • (2006) FEBS Lett , vol.580 , pp. 6837-6845
    • Yi, L.Z.1    He, J.2    Liang, Y.Z.3    Yuan, D.L.4    Chau, F.T.5
  • 6
    • 0029133235 scopus 로고
    • Metabolic effects of metformin in non-insulin-dependent diabetes mellitus
    • Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 1995;333:550-554
    • (1995) N Engl J Med , vol.333 , pp. 550-554
    • Stumvoll, M.1    Nurjhan, N.2    Perriello, G.3    Dailey, G.4    Gerich, J.E.5
  • 7
    • 65949087032 scopus 로고    scopus 로고
    • Lipotoxicity: Why do saturated fatty acids cause and monounsaturates protect against it?
    • Nolan CJ, Larter CZ. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J Gastroenterol Hepatol 2009;24:703-706
    • (2009) J Gastroenterol Hepatol , vol.24 , pp. 703-706
    • Nolan, C.J.1    Larter, C.Z.2
  • 8
    • 0033793133 scopus 로고    scopus 로고
    • Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammation
    • Chinetti G, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm Res 2000;49:497-505
    • (2000) Inflamm Res , vol.49 , pp. 497-505
    • Chinetti, G.1    Fruchart, J.C.2    Staels, B.3
  • 11
    • 0031698177 scopus 로고    scopus 로고
    • Thiazolidinediones-Tools for the research of metabolic syndrome X
    • Komers R, Vrána A. Thiazolidinediones-tools for the research of metabolic syndrome X. Physiol Res 1998;47:215-225
    • (1998) Physiol Res , vol.47 , pp. 215-225
    • Komers, R.1    Vrána, A.2
  • 12
    • 79960058644 scopus 로고    scopus 로고
    • Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-g-dependent activity
    • Toyama K, Nakamura T, Kataoka K, et al. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-g-dependent activity. Biochem Biophys Res Commun 2011;410: 508-513
    • (2011) Biochem Biophys Res Commun , vol.410 , pp. 508-513
    • Toyama, K.1    Nakamura, T.2    Kataoka, K.3
  • 13
    • 84861043519 scopus 로고    scopus 로고
    • It is all in the blood: The multifaceted contribution of circulating progenitor cells in diabetic complications
    • Fadini GP, Avogaro A. It is all in the blood: the multifaceted contribution of circulating progenitor cells in diabetic complications. Exp Diabetes Res 2012;2012:742976
    • (2012) Exp Diabetes Res , vol.2012 , pp. 742976
    • Fadini, G.P.1    Avogaro, A.2
  • 14
    • 39449102532 scopus 로고    scopus 로고
    • Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature
    • Duan SZ, Usher MG, Mortensen RM. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ Res 2008;102: 283-294
    • (2008) Circ Res , vol.102 , pp. 283-294
    • Duan, S.Z.1    Usher, M.G.2    Mortensen, R.M.3
  • 15
    • 33845205804 scopus 로고    scopus 로고
    • Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus
    • Wang CH, Ting MK, Verma S, et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J 2006;152:1051.e1-e8
    • (2006) Am Heart J , vol.152
    • Wang, C.H.1    Ting, M.K.2    Verma, S.3
  • 16
    • 67349155584 scopus 로고    scopus 로고
    • Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease
    • Robinson E, Grieve DJ. Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacol Ther 2009;122:246-263
    • (2009) Pharmacol Ther , vol.122 , pp. 246-263
    • Robinson, E.1    Grieve, D.J.2
  • 17
    • 66149134117 scopus 로고    scopus 로고
    • Effects of coronary artery disease and percutaneous intervention on the cardiac metabolism of nonesterified fatty acids and insulin: Implications of diabetes mellitus
    • Jaumdally RJ, Lip GY, Patel JV, MacFadyen RJ, Varma C. Effects of coronary artery disease and percutaneous intervention on the cardiac metabolism of nonesterified fatty acids and insulin: Implications of diabetes mellitus. J Intern Med 2009;265:689-697
    • (2009) J Intern Med , vol.265 , pp. 689-697
    • Jaumdally, R.J.1    Lip, G.Y.2    Patel, J.V.3    MacFadyen, R.J.4    Varma, C.5
  • 18
    • 0037434561 scopus 로고    scopus 로고
    • Circulating endothelial progenitor cells, vascular function, and cardiovascular risk
    • Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600
    • (2003) N Engl J Med , vol.348 , pp. 593-600
    • Hill, J.M.1    Zalos, G.2    Halcox, J.P.3
  • 19
    • 41049108669 scopus 로고    scopus 로고
    • Wang-Miao, Niu RC. Palmitic and linoleic acids impair endothelial progenitor cells by inhibition of Akt/eNOS pathway
    • Guo WX, Yang QD, Liu YH, Xie XY, Wang-Miao, Niu RC. Palmitic and linoleic acids impair endothelial progenitor cells by inhibition of Akt/eNOS pathway. Arch Med Res 2008;39:434-442
    • (2008) Arch Med Res , vol.39 , pp. 434-442
    • Guo, W.X.1    Yang, Q.D.2    Liu, Y.H.3    Xie, X.Y.4
  • 20
    • 77952427744 scopus 로고    scopus 로고
    • Palmitic acid promotes endothelial progenitor cells apoptosis via p38 and JNK mitogen-activated protein kinase pathways
    • Jiang H, Liang C, Liu X, et al. Palmitic acid promotes endothelial progenitor cells apoptosis via p38 and JNK mitogen-activated protein kinase pathways. Atherosclerosis 2010;210:71-77
    • (2010) Atherosclerosis , vol.210 , pp. 71-77
    • Jiang, H.1    Liang, C.2    Liu, X.3
  • 21
    • 0030602866 scopus 로고    scopus 로고
    • The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation
    • Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996;1302:93-109
    • (1996) Biochim Biophys Acta , vol.1302 , pp. 93-109
    • Schoonjans, K.1    Staels, B.2    Auwerx, J.3
  • 22
    • 58849163113 scopus 로고    scopus 로고
    • Formation of STAT5/PPARgamma transcriptional complex modulates angiogenic cell bioavailability in diabetes
    • Dentelli P, Trombetta A, Togliatto G, et al. Formation of STAT5/PPARgamma transcriptional complex modulates angiogenic cell bioavailability in diabetes. Arterioscler Thromb Vasc Biol 2009;29:114-120
    • (2009) Arterioscler Thromb Vasc Biol , vol.29 , pp. 114-120
    • Dentelli, P.1    Trombetta, A.2    Togliatto, G.3
  • 23
    • 43049118940 scopus 로고    scopus 로고
    • Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARgamma/STAT5 signaling pathway in macaques
    • Prost S, Le Dantec M, Augé S, et al. Human and simian immunodeficiency viruses deregulate early hematopoiesis through a Nef/PPARgamma/STAT5 signaling pathway in macaques. J Clin Invest 2008;118:1765-1775
    • (2008) J Clin Invest , vol.118 , pp. 1765-1775
    • Prost, S.1    Le Dantec, M.2    Augé, S.3
  • 24
    • 33847348148 scopus 로고    scopus 로고
    • Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals
    • Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007;109:1801-1809
    • (2007) Blood , vol.109 , pp. 1801-1809
    • Yoder, M.C.1    Mead, L.E.2    Prater, D.3
  • 25
    • 79959691141 scopus 로고    scopus 로고
    • MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose-and AGE-mediated vascular cell damage
    • Togliatto G, Trombetta A, Dentelli P, Rosso A, Brizzi MF. MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose-and AGE-mediated vascular cell damage. Diabetologia 2011;54:1930-1940
    • (2011) Diabetologia , vol.54 , pp. 1930-1940
    • Togliatto, G.1    Trombetta, A.2    Dentelli, P.3    Rosso, A.4    Brizzi, M.F.5
  • 26
    • 0025296906 scopus 로고
    • Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes
    • Svedberg J, Björntorp P, Smith U, Lönnroth P. Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes. Diabetes 1990;39:570-574
    • (1990) Diabetes , vol.39 , pp. 570-574
    • Svedberg, J.1    Björntorp, P.2    Smith, U.3    Lönnroth, P.4
  • 27
    • 0017074206 scopus 로고
    • A solvent system for delipidation of plasma or serum without protein precipitation
    • Cham BE, Knowles BR. A solvent system for delipidation of plasma or serum without protein precipitation. J Lipid Res 1976;17:176-181
    • (1976) J Lipid Res , vol.17 , pp. 176-181
    • Cham, B.E.1    Knowles, B.R.2
  • 28
    • 77951156798 scopus 로고    scopus 로고
    • Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes
    • Togliatto G, Trombetta A, Dentelli P, et al. Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes 2010;59:1016-1025
    • (2010) Diabetes , vol.59 , pp. 1016-1025
    • Togliatto, G.1    Trombetta, A.2    Dentelli, P.3
  • 29
    • 47649125701 scopus 로고    scopus 로고
    • Interleukin-3 promotes expansion of hemopoietic-derived CD45+ angiogenic cells and their arterial commitment via STAT5 activation
    • Zeoli A, Dentelli P, Rosso A, et al. Interleukin-3 promotes expansion of hemopoietic-derived CD45+ angiogenic cells and their arterial commitment via STAT5 activation. Blood 2008;112:350-361
    • (2008) Blood , vol.112 , pp. 350-361
    • Zeoli, A.1    Dentelli, P.2    Rosso, A.3
  • 30
    • 0027496114 scopus 로고
    • A common nuclear signal transduction pathway activated by growth factor and cytokine receptors
    • Sadowski HB, Shuai K, Darnell JE Jr, Gilman MZ. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 1993;261:1739-1744
    • (1993) Science , vol.261 , pp. 1739-1744
    • Sadowski, H.B.1    Shuai, K.2    Darnell Jr., J.E.3    Gilman, M.Z.4
  • 31
    • 0031836964 scopus 로고    scopus 로고
    • Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation
    • Onishi M, Nosaka T, Misawa K, et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol 1998;18:3871-3879
    • (1998) Mol Cell Biol , vol.18 , pp. 3871-3879
    • Onishi, M.1    Nosaka, T.2    Misawa, K.3
  • 33
    • 78650305331 scopus 로고    scopus 로고
    • Inhibition of b1 integrin and IL-3Rb common subunit interaction hinders tumour angiogenesis
    • Uberti B, Dentelli P, Rosso A, Defilippi P, Brizzi MF. Inhibition of b1 integrin and IL-3Rb common subunit interaction hinders tumour angiogenesis. Oncogene 2010;29:6581-6590
    • (2010) Oncogene , vol.29 , pp. 6581-6590
    • Uberti, B.1    Dentelli, P.2    Rosso, A.3    Defilippi, P.4    Brizzi, M.F.5
  • 34
    • 0036834915 scopus 로고    scopus 로고
    • The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus
    • Clore JN, Allred J, White D, Li J, Stillman J. The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus. Metabolism 2002;51:1471-1477
    • (2002) Metabolism , vol.51 , pp. 1471-1477
    • Clore, J.N.1    Allred, J.2    White, D.3    Li, J.4    Stillman, J.5
  • 35
    • 70450178050 scopus 로고    scopus 로고
    • Dietary patterns and prevention of type 2 diabetes: From research to clinical practice; A systematic review
    • Kastorini CM, Panagiotakos DB. Dietary patterns and prevention of type 2 diabetes: from research to clinical practice; a systematic review. Curr Diabetes Rev 2009;5:221-227
    • (2009) Curr Diabetes Rev , vol.5 , pp. 221-227
    • Kastorini, C.M.1    Panagiotakos, D.B.2
  • 36
    • 79955758735 scopus 로고    scopus 로고
    • Differential regulation of dihydroceramide desaturase by palmitate versus monounsaturated fatty acids: Implications for insulin resistance
    • Hu W, Ross J, Geng T, Brice SE, Cowart LA. Differential regulation of dihydroceramide desaturase by palmitate versus monounsaturated fatty acids: implications for insulin resistance. J Biol Chem 2011;286: 16596-16605
    • (2011) J Biol Chem , vol.286 , pp. 16596-16605
    • Hu, W.1    Ross, J.2    Geng, T.3    Brice, S.E.4    Cowart, L.A.5
  • 37
    • 28944446431 scopus 로고    scopus 로고
    • The many faces of PPARgamma
    • Lehrke M, Lazar MA. The many faces of PPARgamma. Cell 2005;123:993-999
    • (2005) Cell , vol.123 , pp. 993-999
    • Lehrke, M.1    Lazar, M.A.2
  • 39
    • 1642405252 scopus 로고    scopus 로고
    • Characterization of the human STAT5A and STAT5B promoters: Evidence of a positive and negative mechanism of transcriptional regulation
    • Crispi S, Sanzari E, Monfregola J, et al. Characterization of the human STAT5A and STAT5B promoters: evidence of a positive and negative mechanism of transcriptional regulation. FEBS Lett 2004;562:27-34
    • (2004) FEBS Lett , vol.562 , pp. 27-34
    • Crispi, S.1    Sanzari, E.2    Monfregola, J.3
  • 40
    • 0028352434 scopus 로고
    • The p21 inhibitor of cyclindependent kinases controls DNA replication by interaction with PCNA
    • Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclindependent kinases controls DNA replication by interaction with PCNA. Nature 1994;369:574-578
    • (1994) Nature , vol.369 , pp. 574-578
    • Waga, S.1    Hannon, G.J.2    Beach, D.3    Stillman, B.4
  • 41
    • 0006132932 scopus 로고    scopus 로고
    • Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma
    • Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 1997;94:4318-4323
    • (1997) Proc Natl Acad Sci USA , vol.94 , pp. 4318-4323
    • Kliewer, S.A.1    Sundseth, S.S.2    Jones, S.A.3
  • 42
    • 0030835678 scopus 로고    scopus 로고
    • The organization, promoter analysis, and expression of the human PPARgamma gene
    • Fajas L, Auboeuf D, Raspé E, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 1997;272: 18779-18789
    • (1997) J Biol Chem , vol.272 , pp. 18779-18789
    • Fajas, L.1    Auboeuf, D.2    Raspé, E.3
  • 43
    • 1942471942 scopus 로고    scopus 로고
    • Peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands and angiogenesis
    • Margeli A, Kouraklis G, Theocharis S. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands and angiogenesis. Angiogenesis 2003;6:165-169
    • (2003) Angiogenesis , vol.6 , pp. 165-169
    • Margeli, A.1    Kouraklis, G.2    Theocharis, S.3
  • 44
    • 79953066607 scopus 로고    scopus 로고
    • Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes-A randomized controlled trial
    • Esposito K, Maiorino MI, Di Palo C, et al. Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes-a randomized controlled trial. Diabetes Obes Metab 2011;13:439-445
    • (2011) Diabetes Obes Metab , vol.13 , pp. 439-445
    • Esposito, K.1    Maiorino, M.I.2    Di Palo, C.3
  • 45
    • 34247368097 scopus 로고    scopus 로고
    • The PPARgamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells
    • Gensch C, Clever YP, Werner C, Hanhoun M, Böhm M, Laufs U. The PPARgamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 2007;192:67-74
    • (2007) Atherosclerosis , vol.192 , pp. 67-74
    • Gensch, C.1    Clever, Y.P.2    Werner, C.3    Hanhoun, M.4    Böhm, M.5    Laufs, U.6
  • 47
    • 59649096875 scopus 로고    scopus 로고
    • Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells
    • Artwohl M, Lindenmair A, Sexl V, et al. Different mechanisms of saturated versus polyunsaturated FFA-induced apoptosis in human endothelial cells. J Lipid Res 2008;49:2627-2640
    • (2008) J Lipid Res , vol.49 , pp. 2627-2640
    • Artwohl, M.1    Lindenmair, A.2    Sexl, V.3
  • 48
    • 0037329337 scopus 로고    scopus 로고
    • A functional polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population
    • Meirhaeghe A, Fajas L, Gouilleux F, et al. A functional polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population. Arterioscler Thromb Vasc Biol 2003;23:289-294
    • (2003) Arterioscler Thromb Vasc Biol , vol.23 , pp. 289-294
    • Meirhaeghe, A.1    Fajas, L.2    Gouilleux, F.3
  • 49
    • 0041842552 scopus 로고    scopus 로고
    • Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma
    • Shipley JM, Waxman DJ. Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. Mol Pharmacol 2003;64:355-364
    • (2003) Mol Pharmacol , vol.64 , pp. 355-364
    • Shipley, J.M.1    Waxman, D.J.2
  • 50
    • 4143120196 scopus 로고    scopus 로고
    • ERalpha and STAT5a cross-talk: Interaction through C-terminal portions of the proteins decreases STAT5a phosphorylation, nuclear translocation and DNA-binding
    • Wang Y, Cheng CH. ERalpha and STAT5a cross-talk: interaction through C-terminal portions of the proteins decreases STAT5a phosphorylation, nuclear translocation and DNA-binding. FEBS Lett 2004;572:238-244
    • (2004) FEBS Lett , vol.572 , pp. 238-244
    • Wang, Y.1    Cheng, C.H.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.