克洛素

克洛素
识别号
别名	KL；, entrez:9365, klotho, HFTC3, KLA
外部ID	OMIM：604824 MGI：1101771 HomoloGene：68415 GeneCards：KL
基因位置（人类）
染色体	13号染色体
终止	33,066,143 bp
基因位置（小鼠）
染色体	小鼠5号染色体
终止	150,917,282 bp
基因本体
分子功能	• hydrolase activity, hydrolyzing O-glycosyl compounds; • hormone activity; • beta-glucuronidase activity; • signal transducer activity; • hydrolase activity, acting on glycosyl bonds; • vitamin D binding; • fibroblast growth factor binding; • beta-glucosidase activity; • 水解酶活性; • phosphatidylinositol-4,5-bisphosphate 3-kinase activity; • fibroblast growth factor receptor binding; • 1-phosphatidylinositol-3-kinase activity;
细胞组分	• integral component of membrane; • 膜; • 细胞膜; • integral component of plasma membrane; • 细胞外区域; • apical plasma membrane; • 外排体; • 胞内; • 细胞外空间;
生物学过程	• calcium ion homeostasis; • positive regulation of bone mineralization; • 老化; • MAPK cascade; • positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway; • energy reserve metabolic process; • 代谢; • glycosyl compound metabolic process; • phosphatidylinositol phosphate biosynthetic process; • insulin receptor signaling pathway; • fibroblast growth factor receptor signaling pathway; • phosphatidylinositol-3-phosphate biosynthetic process; • 碳水化合物代谢; • regulation of signaling receptor activity; • positive regulation of protein kinase B signaling; • 分子功能调控;
	Sources:Amigo / QuickGO
直系同源
	9365
	16591
	ENSG00000133116
	ENSMUSG00000058488
	Q9UEF7
	O35082
	NM_004795; NM_153683
	NM_013823
	NP_004786
	NP_038851
	维基数据
查看/编辑人类	查看/编辑小鼠

克洛素（Klotho，或译可罗素）是一种由人类KL基因编码而成的酵素^[5]。

该基因属于第一型跨膜蛋白，且具有β-葡萄糖醛酸苷酶（英语：beta-glucuronidase）活性。慢性肾衰竭患者体内的可罗素制造会减少，这也可能是造成慢性肾衰后一连串并发症的原因（如动脉硬化、骨质疏松、以及皮肤松弛等等）。该编码基因的突变也与老化、骨质流失有关^[6]^[7]。过度表现可罗素的小鼠，寿命会较野生型小鼠长^[8]。

功能

克洛素为一种跨膜蛋白，会调控生物体对于胰岛素的敏感性，且可能也与老化有关。本蛋白最早由黑尾诚等人于1997年发现^[9]，该蛋白命名自希腊神话命运三女神中的克洛托（Klotho）。

克洛素具有β-葡萄糖醛酸苷酶（英语：beta-glucuronidase）活性，可以水解β-葡萄糖醛酸（英语：glucuronide），与人类老化有关^[10]^[11]。血浆中的循环克洛素会随年纪逐渐减少^[12]。β-克洛素会与FGF受体行程协同受体（英语：co-receptor），可与FGF19、FGF20、FGF23等成纤维细胞生长因子（FGF）结合进行作用^[13]^[14]。

克洛素缺乏的小鼠会出现类似人类早衰的症状，并加速动脉血管硬化的进程，同时也会损伤血管新生和内皮调控血管扩张的能力。推论克洛素可能可以透过内皮源性一氧化氮释放来保护心血管系统。

过度表现克洛素的小鼠，平均寿命会较一般小数多出19%至31%^[8]。克洛速基因的某些变异还与长寿和增进认知功能相关^[15]。

克洛素的作用机转迄今未明，目前已知可以透过提升TRPV5（英语：TRPV5）和降低TRPC6（英语：TRPC6）的表达调控细胞的钙平衡^[16]。此外，克洛素也会增加内向整流离子通道ROMK（英语：ROMK）的表达^[16]。克洛素缺乏的小鼠会会增加维他命D的制造^[17]^[18]^[19]^[20]。

参考文献

^ ^1.0 ^1.1 ^1.2 GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017
^ ^2.0 ^2.1 ^2.2 GRCm38: Ensembl release 89: ENSMUSG00000058488 - Ensembl, May 2017
^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochemical and Biophysical Research Communications. Jan 1998, 242 (3): 626–30. PMID 9464267. doi:10.1006/bbrc.1997.8019.
^ Entrez Gene: klotho.
^ Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. 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. 2016, 113 (50): 14372–14377. PMC 5167198 . PMID 27911795. doi:10.1073/pnas.1611243113.
^ ^8.0 ^8.1 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. Suppression of aging in mice by the hormone Klotho. Science. Sep 2005, 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. PMC 2536606 . PMID 16123266. doi:10.1126/science.1112766.
^ 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. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. Nov 1997, 390 (6655): 45–51. Bibcode:1997Natur.390...45K. PMID 9363890. doi:10.1038/36285.
^ Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proceedings of the National Academy of Sciences of the United States of America. Jan 2002, 99 (2): 856–61. Bibcode:2002PNAS...99..856A. PMC 117395 . PMID 11792841. doi:10.1073/pnas.022484299.
^ Rodriguez T. Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy. Journal of Molecular Biology Research. 2015, 5 (1): 11. doi:10.5539/jmbr.v5n1p11.
^ Xiao NM, Zhang YM, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chinese Medical Journal. May 2004, 117 (5): 742–7. PMID 15161545. ^{[永久失效链接]}
^ Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Reviews. 2015, 34 (3): 479–96. PMC 4573649 . PMID 26224133. doi:10.1007/s10555-015-9579-8.
^ 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. FGF21 Regulates Sweet and Alcohol Preference. Cell Metabolism. February 2016, 23 (2): 344–9. PMC 4749404 . PMID 26724861. doi:10.1016/j.cmet.2015.12.008.
^ Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)
^ ^16.0 ^16.1 Huang CL. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International. May 2010, 77 (10): 855–60. PMID 20375979. doi:10.1038/ki.2010.73.
^ Kuro-o M. Klotho and aging. Biochimica et Biophysica Acta. Oct 2009, 1790 (10): 1049–58. PMC 2743784 . PMID 19230844. doi:10.1016/j.bbagen.2009.02.005.
^ Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. The Journal of Cell Biology. Aug 2008, 182 (3): 459–65. PMC 2500132 . PMID 18678710. doi:10.1083/jcb.200803024.
^ Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Molecular Endocrinology. Dec 2003, 17 (12): 2393–403. PMID 14528024. doi:10.1210/me.2003-0048.
^ Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. alpha-Klotho as a regulator of calcium homeostasis. Science. Jun 2007, 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. PMID 17569864. doi:10.1126/science.1135901.

延伸阅读

Shimoyama Y, Taki K, Mitsuda Y, Tsuruta Y, Hamajima N, Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients. American Journal of Nephrology. 2009, 30 (4): 383–8. PMID 19690404. doi:10.1159/000235686.
Choi BH, Kim CG, Lim Y, Lee YH, Shin SY. Transcriptional activation of the human Klotho gene by epidermal growth factor in HEK293 cells; role of Egr-1. Gene. Jan 2010, 450 (1–2): 121–7. PMID 19913601. doi:10.1016/j.gene.2009.11.004.
Fukumoto S. [Chronic kidney disease (CKD) and bone. Regulation of calcium and phosphate metabolism by FGF23/Klotho]. Clinical Calcium. Apr 2009, 19 (4): 523–8. PMID 19329831.
Nabeshima Y. Challenge of overcoming aging-related disorders. Journal of Dermatological Science. Dec 2000,. 24 Suppl 1: S15–21. PMID 11137391. doi:10.1016/S0923-1811(00)00136-5.
Razzaque MS. FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player?. American Journal of Physiology. Renal Physiology. Mar 2009, 296 (3): F470–6. PMC 2660189 . PMID 19019915. doi:10.1152/ajprenal.90538.2008.
Menon R, Pearce B, Velez DR, Merialdi M, Williams SM, Fortunato SJ, Thorsen P. Racial disparity in pathophysiologic pathways of preterm birth based on genetic variants. Reproductive Biology and Endocrinology. 2009, 7: 62. PMC 2714850 . PMID 19527514. doi:10.1186/1477-7827-7-62.
Prié D, Ureña Torres P, Friedlander G. [Fibroblast Growth Factor 23-Klotho: a new axis of phosphate balance control]. Médecine Sciences. May 2009, 25 (5): 489–95. PMID 19480830. doi:10.1051/medsci/2009255489.
Torres PU, Prié D, Beck L, De Brauwere D, Leroy C, Friedlander G. Klotho gene, phosphocalcic metabolism, and survival in dialysis. Journal of Renal Nutrition. Jan 2009, 19 (1): 50–6. PMID 19121771. doi:10.1053/j.jrn.2008.10.018.
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. Mary Bridger J , 编. Genetic variation in healthy oldest-old. PLOS ONE. 2009, 4 (8): e6641. Bibcode:2009PLoSO...4.6641H. PMC 2722017 . PMID 19680556. doi:10.1371/journal.pone.0006641.
Shimoyama Y, Nishio K, Hamajima N, Niwa T. 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. Clinica Chimica Acta; International Journal of Clinical Chemistry. Aug 2009, 406 (1–2): 134–8. PMID 19539617. doi:10.1016/j.cca.2009.06.011.
Wang HL, Xu Q, Wang Z, Zhang YH, Si LY, Li XJ, Yang QH, Xiao H. A potential regulatory single nucleotide polymorphism in the promoter of the Klotho gene may be associated with essential hypertension in the Chinese Han population. Clinica Chimica Acta; International Journal of Clinical Chemistry. Mar 2010, 411 (5–6): 386–90. PMID 20005218. doi:10.1016/j.cca.2009.12.004.
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. High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. Journal of Bone and Mineral Research. Dec 2009, 24 (12): 2039–49. PMC 2791518 . PMID 19453261. doi:10.1359/jbmr.090524.
Torres PU, Prié D, Molina-Blétry V, Beck L, Silve C, Friedlander G. Klotho: an antiaging protein involved in mineral and vitamin D metabolism. Kidney International. Apr 2007, 71 (8): 730–7. PMID 17332731. doi:10.1038/sj.ki.5002163.
Kurosu H, Kuro-o M. The Klotho gene family and the endocrine fibroblast growth factors. Current Opinion in Nephrology and Hypertension. Jul 2008, 17 (4): 368–72. PMID 18660672. doi:10.1097/MNH.0b013e3282ffd994.
Kuro-o M. Klotho and aging. Biochimica et Biophysica Acta. Oct 2009, 1790 (10): 1049–58. PMC 2743784 . PMID 19230844. doi:10.1016/j.bbagen.2009.02.005.
Wolf I, Laitman Y, Rubinek T, Abramovitz L, Novikov I, Beeri R, Kuro-O M, Koeffler HP, Catane R, Freedman LS, Levy-Lahad E, Karlan BY, Friedman E, Kaufman B. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Oncogene. Jan 2010, 29 (1): 26–33. PMID 19802015. doi:10.1038/onc.2009.301.
Invidia L, Salvioli S, Altilia S, Pierini M, Panourgia MP, Monti D, De Rango F, Passarino G, Franceschi C. The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect. Biogerontology. Feb 2010, 11 (1): 67–73. PMID 19421891. doi:10.1007/s10522-009-9229-z.
Nabeshima Y. [Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]. Clinical Calcium. Jul 2008, 18 (7): 923–34. PMID 18591743.
Chen SN, Cilingiroglu M, Todd J, Lombardi R, Willerson JT, Gotto AM, Ballantyne CM, Marian AJ. Candidate genetic analysis of plasma high-density lipoprotein-cholesterol and severity of coronary atherosclerosis. BMC Medical Genetics. 2009, 10: 111. PMC 2775733 . PMID 19878569. doi:10.1186/1471-2350-10-111.
Zhang R, Zheng F. PPAR-gamma and aging: one link through klotho?. Kidney International. Sep 2008, 74 (6): 702–4. PMID 18756295. doi:10.1038/ki.2008.382.

外部链接

Entrez Gene entry for Klotho
GenAge entry for Klotho （页面存档备份，存于互联网档案馆）

克洛素引用了美国国家医学图书馆提供的资料，这些资料属于公共领域。

[refGRCh38Ensembl-1] 1.0 ^1.1 ^1.2 GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017

[refGRCm38Ensembl-2] 2.0 ^2.1 ^2.2 GRCm38: Ensembl release 89: ENSMUSG00000058488 - Ensembl, May 2017

[3] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9464267-5] Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochemical and Biophysical Research Communications. Jan 1998, 242 (3): 626–30. PMID 9464267. doi:10.1006/bbrc.1997.8019.

[entrez-6] Entrez Gene: klotho.

[SchumannLiu2016-7] Schumann G, Liu C, O'Reilly P, Gao H, Song P, Xu B, et al. 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. 2016, 113 (50): 14372–14377. PMC 5167198 . PMID 27911795. doi:10.1073/pnas.1611243113.

[pmid16123266-8] 8.0 ^8.1 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. Suppression of aging in mice by the hormone Klotho. Science. Sep 2005, 309 (5742): 1829–33. Bibcode:2005Sci...309.1829K. PMC 2536606 . PMID 16123266. doi:10.1126/science.1112766.

[pmid9363890-9] 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. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. Nov 1997, 390 (6655): 45–51. Bibcode:1997Natur.390...45K. PMID 9363890. doi:10.1038/36285.

[pmid11792841-10] Arking DE, Krebsova A, Macek M, Macek M, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proceedings of the National Academy of Sciences of the United States of America. Jan 2002, 99 (2): 856–61. Bibcode:2002PNAS...99..856A. PMC 117395 . PMID 11792841. doi:10.1073/pnas.022484299.

[11] Rodriguez T. Identifying significant biological markers in Klotho gene variants across wide ranging taxonomy. Journal of Molecular Biology Research. 2015, 5 (1): 11. doi:10.5539/jmbr.v5n1p11.

[pmid15161545-12] Xiao NM, Zhang YM, Zheng Q, Gu J. Klotho is a serum factor related to human aging. Chinese Medical Journal. May 2004, 117 (5): 742–7. PMID 15161545. ^{[永久失效链接]}

[pmid26224133-13] Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Reviews. 2015, 34 (3): 479–96. PMC 4573649 . PMID 26224133. doi:10.1007/s10555-015-9579-8.

[FGF21_receptor_expression_in_the_brain-14] 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. FGF21 Regulates Sweet and Alcohol Preference. Cell Metabolism. February 2016, 23 (2): 344–9. PMC 4749404 . PMID 26724861. doi:10.1016/j.cmet.2015.12.008.

[15] Dena B. Dubal et al., Life Extension Factor Klotho Enhances Cognition, Cell Reports, 2014, DOI: 10.1016/j.celrep.2014.03.076 (open access)

[Huang_et_al_2010-16] 16.0 ^16.1 Huang CL. Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney International. May 2010, 77 (10): 855–60. PMID 20375979. doi:10.1038/ki.2010.73.

[17] Kuro-o M. Klotho and aging. Biochimica et Biophysica Acta. Oct 2009, 1790 (10): 1049–58. PMC 2743784 . PMID 19230844. doi:10.1016/j.bbagen.2009.02.005.

[18] Medici D, Razzaque MS, Deluca S, Rector TL, Hou B, Kang K, Goetz R, Mohammadi M, Kuro-O M, Olsen BR, Lanske B. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis. The Journal of Cell Biology. Aug 2008, 182 (3): 459–65. PMC 2500132 . PMID 18678710. doi:10.1083/jcb.200803024.

[pmid14528024-19] Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Molecular Endocrinology. Dec 2003, 17 (12): 2393–403. PMID 14528024. doi:10.1210/me.2003-0048.

[pmid17569864-20] Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K, Tominaga M, Kita N, Tomiyama K, Iijima J, Nabeshima Y, Fujioka M, Asato R, Tanaka S, Kojima K, Ito J, Nozaki K, Hashimoto N, Ito T, Nishio T, Uchiyama T, Fujimori T, Nabeshima Y. alpha-Klotho as a regulator of calcium homeostasis. Science. Jun 2007, 316 (5831): 1615–8. Bibcode:2007Sci...316.1615I. PMID 17569864. doi:10.1126/science.1135901.

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