Klotho (biology): Difference between revisions

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'''Klotho''' is an [[enzyme]] that in humans is encoded by the KL [[gene]].<ref name="pmid9464267">{{cite journal | vauthors = Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y | title = Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein | journal = Biochemical and Biophysical Research Communications | volume = 242 | issue = 3 | pages = 626–30 | date = Jan 1998 | pmid = 9464267 | doi = 10.1006/bbrc.1997.8019 }}</ref>
'''Klotho''' is an [[enzyme]] that in humans is encoded by the KL [[gene]].<ref name="pmid9464267">{{cite journal | vauthors = Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y | title = Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein | journal = Biochemical and Biophysical Research Communications | volume = 242 | issue = 3 | pages = 626–30 | date = Jan 1998 | pmid = 9464267 | doi = 10.1006/bbrc.1997.8019 }}</ref>


This gene encodes a type-I membrane protein that is related to [[beta-glucuronidase|β-glucuronidase]]s. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.<ref name="entrez">{{cite web | title = Entrez Gene: klotho| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9365| accessdate = }}</ref><ref name="SchumannLiu2016">{{cite journal | vauthors = Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura Lepe M, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hällfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson Å, Joshi PK, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikäinen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schraut K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, de Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimäki T, Liu Y, Madden PA, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, van der Harst P, van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivières S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott P | display-authors = 6 | title = KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue=50 | year = 2016 | pages = 14372–14377 | pmid = 27911795 | doi = 10.1073/pnas.1611243113 }}</ref> Transgenic mice that overexpress Klotho live longer than wild-type mice.<ref name="pmid16123266"/>
This gene encodes a type-I membrane protein that is related to [[beta-glucuronidase|β-glucuronidase]]s. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.<ref name="entrez">{{cite web | title = Entrez Gene: klotho| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9365| accessdate = }}</ref><ref name="SchumannLiu2016">{{cite journal | vauthors = Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, Ruggeri B, Amin N, Jia T, Preis S, Segura Lepe M, Akira S, Barbieri C, Baumeister S, Cauchi S, Clarke TK, Enroth S, Fischer K, Hällfors J, Harris SE, Hieber S, Hofer E, Hottenga JJ, Johansson Å, Joshi PK, Kaartinen N, Laitinen J, Lemaitre R, Loukola A, Luan J, Lyytikäinen LP, Mangino M, Manichaikul A, Mbarek H, Milaneschi Y, Moayyeri A, Mukamal K, Nelson C, Nettleton J, Partinen E, Rawal R, Robino A, Rose L, Sala C, Satoh T, Schmidt R, Schraut K, Scott R, Smith AV, Starr JM, Teumer A, Trompet S, Uitterlinden AG, Venturini C, Vergnaud AC, Verweij N, Vitart V, Vuckovic D, Wedenoja J, Yengo L, Yu B, Zhang W, Zhao JH, Boomsma DI, Chambers J, Chasman DI, Daniela T, de Geus E, Deary I, Eriksson JG, Esko T, Eulenburg V, Franco OH, Froguel P, Gieger C, Grabe HJ, Gudnason V, Gyllensten U, Harris TB, Hartikainen AL, Heath AC, Hocking L, Hofman A, Huth C, Jarvelin MR, Jukema JW, Kaprio J, Kooner JS, Kutalik Z, Lahti J, Langenberg C, Lehtimäki T, Liu Y, Madden PA, Martin N, Morrison A, Penninx B, Pirastu N, Psaty B, Raitakari O, Ridker P, Rose R, Rotter JI, Samani NJ, Schmidt H, Spector TD, Stott D, Strachan D, Tzoulaki I, van der Harst P, van Duijn CM, Marques-Vidal P, Vollenweider P, Wareham NJ, Whitfield JB, Wilson J, Wolffenbuttel B, Bakalkin G, Evangelou E, Liu Y, Rice KM, Desrivières S, Kliewer SA, Mangelsdorf DJ, Müller CP, Levy D, Elliott P | display-authors = 6 | title = KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue=50 | year = 2016 | pages = 14372–14377 | pmid = 27911795 | doi = 10.1073/pnas.1611243113 | pmc=5167198}}</ref> Transgenic mice that overexpress Klotho live longer than wild-type mice.<ref name="pmid16123266"/>
 


== Function ==
== Function ==


Klotho is a [[transmembrane protein]] that, in addition to other effects, provides some control over the sensitivity of the organism to [[insulin]] and appears to be involved in [[aging]]. Its discovery was documented in 1997 by Kuro-o ''et al.''<ref name="pmid9363890">{{cite journal | vauthors = Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI | title = Mutation of the mouse klotho gene leads to a syndrome resembling ageing | journal = Nature | volume = 390 | issue = 6655 | pages = 45–51 | date = Nov 1997 | pmid = 9363890 | doi = 10.1038/36285 | bibcode = 1997Natur.390...45K }}</ref> The name of the gene comes from Klotho or [[Clotho]], one of the [[Moirai]], or Fates, in [[Greek mythology]].
Klotho is a [[transmembrane protein]] that, in addition to other effects, provides some control over the sensitivity of the organism to [[insulin]] and appears to be involved in [[ageing]]. Its discovery was documented in 1997 by Kuro-o ''et al.''<ref name="pmid9363890">{{cite journal | vauthors = Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI | title = Mutation of the mouse klotho gene leads to a syndrome resembling ageing | journal = Nature | volume = 390 | issue = 6655 | pages = 45–51 | date = Nov 1997 | pmid = 9363890 | doi = 10.1038/36285 | bibcode = 1997Natur.390...45K }}</ref> The name of the gene comes from Klotho or [[Clotho]], one of the [[Moirai]], or Fates, in [[Greek mythology]].


The Klotho protein is a novel [[beta-glucosidase|β-glucuronidase]] ([[Enzyme Commission number|EC number]] 3.2.1.31) capable of hydrolyzing [[steroid]] [[glucuronide|β-glucuronides]]. Genetic variants in ''KLOTHO'' have been associated with human aging,<ref name="pmid11792841">{{cite journal | vauthors = Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC | title = Association of human aging with a functional variant of klotho | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 2 | pages = 856–61 | date = Jan 2002 | pmid = 11792841 | pmc = 117395 | doi = 10.1073/pnas.022484299 | bibcode = 2002PNAS...99..856A }}</ref><ref>Rodriguez, T. (2015). Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy. Journal of Molecular Biology Research, 5(1), p11.</ref> and Klotho protein has been shown to be a circulating factor detectable in [[blood plasma|serum]] that declines with age.<ref name="pmid15161545">{{cite journal | vauthors = Xiao NM, Zhang YM, Zheng Q, Gu J | title = Klotho is a serum factor related to human aging | journal = Chinese Medical Journal | volume = 117 | issue = 5 | pages = 742–7 | date = May 2004 | pmid = 15161545 | doi =  | url = http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2004&vol=117&issue=5&beginpage=742 }}</ref>
The Klotho protein is a novel [[beta-glucosidase|β-glucuronidase]] ([[Enzyme Commission number|EC number]] 3.2.1.31) capable of hydrolyzing [[steroid]] [[glucuronide|β-glucuronides]]. Genetic variants in ''KLOTHO'' have been associated with human aging,<ref name="pmid11792841">{{cite journal | vauthors = Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC | title = Association of human aging with a functional variant of klotho | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 2 | pages = 856–61 | date = Jan 2002 | pmid = 11792841 | pmc = 117395 | doi = 10.1073/pnas.022484299 | bibcode = 2002PNAS...99..856A }}</ref><ref>{{cite journal | vauthors = Rodriguez T | year = 2015 | title = Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy | url = | journal = Journal of Molecular Biology Research | volume = 5 | issue = 1| page = 11 | doi=10.5539/jmbr.v5n1p11}}</ref> and Klotho protein has been shown to be a circulating factor detectable in [[blood plasma|serum]] that declines with age.<ref name="pmid15161545">{{cite journal | vauthors = Xiao NM, Zhang YM, Zheng Q, Gu J | title = Klotho is a serum factor related to human aging | journal = Chinese Medical Journal | volume = 117 | issue = 5 | pages = 742–7 | date = May 2004 | pmid = 15161545 | doi =  | url = http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2004&vol=117&issue=5&beginpage=742 }}{{dead link|date=December 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>


The binding of certain [[fibroblast growth factor]]s (FGF's) viz., FGF19, FGF20, and FGR23, to their [[Fibroblast growth factor receptor]]s, is promoted by their interaction with Klotho.<ref name="pmid26224133">{{cite journal | vauthors = Helsten T, Schwaederle M, Kurzrock R | title = Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications | journal = Cancer Metastasis Reviews | volume = 34 | issue = 3 | pages = 479–96 | year = 2015 | pmid = 26224133 | pmc = 4573649 | doi = 10.1007/s10555-015-9579-8 | url = }}</ref>
The binding of certain [[fibroblast growth factor]]s (FGF's) viz., FGF19, FGF20, and FGF23, to their [[fibroblast growth factor receptor]]s, is promoted via their interactions as [[co-receptor]]s with β-Klotho.<ref name="pmid26224133">{{cite journal | vauthors = Helsten T, Schwaederle M, Kurzrock R | title = Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications | journal = Cancer Metastasis Reviews | volume = 34 | issue = 3 | pages = 479–96 | year = 2015 | pmid = 26224133 | pmc = 4573649 | doi = 10.1007/s10555-015-9579-8 | url = }}</ref><ref name="FGF21 receptor expression in the brain">{{cite journal | vauthors = Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA | title = FGF21 Regulates Sweet and Alcohol Preference | journal = Cell Metabolism | volume = 23 | issue = 2 | pages = 344–9 | date = February 2016 | pmid = 26724861 | pmc = 4749404 | doi = 10.1016/j.cmet.2015.12.008 | url = }}</ref>


Klotho-deficient mice manifest a [[syndrome]] resembling accelerated human aging and display extensive and accelerated [[arteriosclerosis]]. Additionally, they exhibit impaired [[endothelium]] dependent [[vasodilation]] and impaired [[angiogenesis]], suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived [[Nitric oxide|NO]] production.
Klotho-deficient mice manifest a [[syndrome]] resembling accelerated human aging and display extensive and accelerated [[arteriosclerosis]]. Additionally, they exhibit impaired [[endothelium]] dependent [[vasodilation]] and impaired [[angiogenesis]], suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived [[Nitric oxide|NO]] production.
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{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T | title = KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients | journal = American Journal of Nephrology | volume = 30 | issue = 4 | pages = 383–8 | year = 2009 | pmid = 19690404 | doi = 10.1159/000235686 }}
* {{cite journal | vauthors = Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T | title = KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients | journal = American Journal of Nephrology | volume = 30 | issue = 4 | pages = 383–8 | year = 2009 | pmid = 19690404 | doi = 10.1159/000235686 }}
* {{cite journal | vauthors = Choi BH, Kim CG, Lim Y, Lee YH, Shin SY | title = Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1 | journal = Gene | volume = 450 | issue = 1-2 | pages = 121–7 | date = Jan 2010 | pmid = 19913601 | doi = 10.1016/j.gene.2009.11.004 }}
* {{cite journal | vauthors = Choi BH, Kim CG, Lim Y, Lee YH, Shin SY | title = Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1 | journal = Gene | volume = 450 | issue = 1–2 | pages = 121–7 | date = Jan 2010 | pmid = 19913601 | doi = 10.1016/j.gene.2009.11.004 }}
* {{cite journal | vauthors = Fukumoto S | title = [Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho] | journal = Clinical Calcium | volume = 19 | issue = 4 | pages = 523–8 | date = Apr 2009 | pmid = 19329831 | doi = }}
* {{cite journal | vauthors = Fukumoto S | title = [Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho] | journal = Clinical Calcium | volume = 19 | issue = 4 | pages = 523–8 | date = Apr 2009 | pmid = 19329831 | doi = }}
* {{cite journal | vauthors = Nabeshima Y | title = Challenge of overcoming aging-related disorders | journal = Journal of Dermatological Science | volume = 24 Suppl 1 | issue =  | pages = S15-21 | date = Dec 2000 | pmid = 11137391 | doi = 10.1016/S0923-1811(00)00136-5 }}
* {{cite journal | vauthors = Nabeshima Y | title = Challenge of overcoming aging-related disorders | journal = Journal of Dermatological Science | volume = 24 Suppl 1 | issue =  | pages = S15-21 | date = Dec 2000 | pmid = 11137391 | doi = 10.1016/S0923-1811(00)00136-5 }}
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* {{cite journal | vauthors = Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G | title = Klotho gene, phosphocalcic metabolism, and survival in dialysis | journal = Journal of Renal Nutrition | volume = 19 | issue = 1 | pages = 50–6 | date = Jan 2009 | pmid = 19121771 | doi = 10.1053/j.jrn.2008.10.018 }}
* {{cite journal | vauthors = Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G | title = Klotho gene, phosphocalcic metabolism, and survival in dialysis | journal = Journal of Renal Nutrition | volume = 19 | issue = 1 | pages = 50–6 | date = Jan 2009 | pmid = 19121771 | doi = 10.1053/j.jrn.2008.10.018 }}
* {{cite journal | vauthors = Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, Pieczyk M, Sailer C, Kollar A, Thomas R, Agalaridis G, Yamada S, Oliveira L, Collins JA, Meneilly G, Marra MA, Madden KM, Le ND, Connors JM, Brooks-Wilson AR | title = Genetic variation in healthy oldest-old | journal = PLOS ONE | volume = 4 | issue = 8 | pages = e6641 | year = 2009 | pmid = 19680556 | pmc = 2722017 | doi = 10.1371/journal.pone.0006641 | editor1-last = Mary Bridger | bibcode = 2009PLoSO...4.6641H | editor1-first = Joanna }}
* {{cite journal | vauthors = Halaschek-Wiener J, Amirabbasi-Beik M, Monfared N, Pieczyk M, Sailer C, Kollar A, Thomas R, Agalaridis G, Yamada S, Oliveira L, Collins JA, Meneilly G, Marra MA, Madden KM, Le ND, Connors JM, Brooks-Wilson AR | title = Genetic variation in healthy oldest-old | journal = PLOS ONE | volume = 4 | issue = 8 | pages = e6641 | year = 2009 | pmid = 19680556 | pmc = 2722017 | doi = 10.1371/journal.pone.0006641 | editor1-last = Mary Bridger | bibcode = 2009PLoSO...4.6641H | editor1-first = Joanna }}
* {{cite journal | vauthors = Shimoyama Y, Nishio K, Hamajima N, Niwa T | title = KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 406 | issue = 1-2 | pages = 134–8 | date = Aug 2009 | pmid = 19539617 | doi = 10.1016/j.cca.2009.06.011 }}
* {{cite journal | vauthors = Shimoyama Y, Nishio K, Hamajima N, Niwa T | title = KLOTHO gene polymorphisms G-395A and C1818T are associated with lipid and glucose metabolism, bone mineral density and systolic blood pressure in Japanese healthy subjects | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 406 | issue = 1–2 | pages = 134–8 | date = Aug 2009 | pmid = 19539617 | doi = 10.1016/j.cca.2009.06.011 }}
* {{cite journal | vauthors = Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H | title = A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 411 | issue = 5-6 | pages = 386–90 | date = Mar 2010 | pmid = 20005218 | doi = 10.1016/j.cca.2009.12.004 }}
* {{cite journal | vauthors = Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H | title = A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 411 | issue = 5–6 | pages = 386–90 | date = Mar 2010 | pmid = 20005218 | doi = 10.1016/j.cca.2009.12.004 }}
* {{cite journal | vauthors = Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM | title = High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men | journal = Journal of Bone and Mineral Research | volume = 24 | issue = 12 | pages = 2039–49 | date = Dec 2009 | pmid = 19453261 | pmc = 2791518 | doi = 10.1359/jbmr.090524 }}
* {{cite journal | vauthors = Yerges LM, Klei L, Cauley JA, Roeder K, Kammerer CM, Moffett SP, Ensrud KE, Nestlerode CS, Marshall LM, Hoffman AR, Lewis C, Lang TF, Barrett-Connor E, Ferrell RE, Orwoll ES, Zmuda JM | title = High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men | journal = Journal of Bone and Mineral Research | volume = 24 | issue = 12 | pages = 2039–49 | date = Dec 2009 | pmid = 19453261 | pmc = 2791518 | doi = 10.1359/jbmr.090524 }}
* {{cite journal | vauthors = Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G | title = Klotho: an antiaging protein involved in mineral and vitamin D metabolism | journal = Kidney International | volume = 71 | issue = 8 | pages = 730–7 | date = Apr 2007 | pmid = 17332731 | doi = 10.1038/sj.ki.5002163 }}
* {{cite journal | vauthors = Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G | title = Klotho: an antiaging protein involved in mineral and vitamin D metabolism | journal = Kidney International | volume = 71 | issue = 8 | pages = 730–7 | date = Apr 2007 | pmid = 17332731 | doi = 10.1038/sj.ki.5002163 }}
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[[Category:Gerontology]]
[[Category:Gerontology]]
[[Category:EC 3.2.1]]
[[Category:EC 3.2.1]]
[[Category:Human genes]]

Latest revision as of 11:29, 9 January 2019

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Identifiers
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Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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View/Edit Human

Klotho is an enzyme that in humans is encoded by the KL gene.[1]

This gene encodes a type-I membrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing, bone loss and alcohol consumption.[2][3] Transgenic mice that overexpress Klotho live longer than wild-type mice.[4]

Function

Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. Its discovery was documented in 1997 by Kuro-o et al.[5] The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.

The Klotho protein is a novel β-glucuronidase (EC number 3.2.1.31) capable of hydrolyzing steroid β-glucuronides. Genetic variants in KLOTHO have been associated with human aging,[6][7] and Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[8]

The binding of certain fibroblast growth factors (FGF's) viz., FGF19, FGF20, and FGF23, to their fibroblast growth factor receptors, is promoted via their interactions as co-receptors with β-Klotho.[9][10]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

Although the vast majority of research has been based on lack of Klotho, it was demonstrated that an overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[4] In addition, variations in the Klotho gene (SNP Rs9536314) are associated with both life extension and increased cognition in human populations.[11]

The mechanism of action of klotho is not fully understood, but it changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5 and decreasing that of TRPC6.[12] Additionally, klotho increases membrane expression of the inward rectifier channel ROMK.[12] Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[13][14][15][16]

References

  1. ↑ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y (Jan 1998). "Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein". Biochemical and Biophysical Research Communications. 242 (3): 626–30. doi:10.1006/bbrc.1997.8019. PMID 9464267.
  2. ↑ "Entrez Gene: klotho".
  3. ↑ Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. (2016). "KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference". Proceedings of the National Academy of Sciences of the United States of America. 113 (50): 14372–14377. doi:10.1073/pnas.1611243113. PMC 5167198. PMID 27911795.
  4. ↑ 4.0 4.1 Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (Sep 2005). "Suppression of aging in mice by the hormone Klotho". Science. 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. doi:10.1126/science.1112766. PMC 2536606. PMID 16123266.
  5. ↑ Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (Nov 1997). "Mutation of the mouse klotho gene leads to a syndrome resembling ageing". Nature. 390 (6655): 45–51. Bibcode:1997Natur.390...45K. doi:10.1038/36285. PMID 9363890.
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Further reading

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