克洛素

克洛素（Klotho，或譯可羅素）是一種由人類KL基因編碼而成的酵素^[5]。

克洛素
識別號
別名	KL；, entrez:9365, klotho, HFTC3, KLA
外部ID	OMIM：604824 MGI：1101771 HomoloGene：68415 GeneCards：KL
基因位置（人類） 染色體 13號染色體[1] 基因座 13q13.1 起始 33,016,423 bp[1] 終止 33,066,143 bp[1]
基因位置（小鼠） 染色體 小鼠5號染色體[2] 基因座 5|5 G3 起始 150,876,072 bp[2] 終止 150,917,282 bp[2]
基因本體 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 細胞組分 • integral component of membrane • 膜 • 細胞膜 • integral component of plasma membrane • 細胞外區域 • apical plasma membrane • 外排體 • 胞內 • 細胞外空間 生物學過程 • 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 • 代謝 • glycosyl compound metabolic process • phosphatidylinositol phosphate biosynthetic process • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • phosphatidylinositol-3-phosphate biosynthetic process • 碳水化合物代謝 • regulation of signaling receptor activity • positive regulation of protein kinase B signaling • 分子功能調控 Sources:Amigo / QuickGO
直系同源
物種	人類	小鼠
Entrez	9365	16591
Ensembl	ENSG00000133116	ENSMUSG00000058488
UniProt	Q9UEF7	O35082
mRNA​序列	​NM_004795 ​NM_153683	NM_013823
蛋白序列	NP_004786	NP_038851
基因位置​（UCSC）	Chr 13: 33.02 – 33.07 Mb	Chr 5: 150.88 – 150.92 Mb
PubMed​查找	[3]	[4]
維基數據
檢視/編輯人類 檢視/編輯小鼠

該基因屬於第一型跨膜蛋白，且具有β-葡萄糖醛酸苷酶（英語：beta-glucuronidase）活性。慢性腎衰竭患者體內的可羅素製造會減少，這也可能是造成慢性腎衰後一連串併發症的原因（如動脈硬化、骨質疏鬆、以及皮膚鬆弛等等）。該編碼基因的突變也與老化、骨質流失有關^[6][7]。過度表現可羅素的小鼠，壽命會較野生型小鼠長^[8]。

功能

克洛素為一種跨膜蛋白，會調控生物體對於胰島素的敏感性，且可能也與老化有關。本蛋白最早由黑尾誠等人於1997年發現^[9]，該蛋白命名自希臘神話命運三女神中的克洛托（Klotho）。

克洛素具有β-葡萄糖醛酸苷酶（英語：beta-glucuronidase）活性，可以水解β-葡萄糖醛酸（英語：glucuronide），與人類老化有關^[10][11]。血漿中的循環克洛素會隨年紀逐漸減少^[12]。β-克洛素會與FGF受體行程協同受體（英語：co-receptor），可與FGF19、FGF20、FGF23等成纖維細胞生長因子（FGF）結合進行作用^[13][14]。

克洛素缺乏的小鼠會出現類似人類早衰的症狀，並加速動脈血管硬化的進程，同時也會損傷血管新生和內皮調控血管擴張的能力。推論克洛素可能可以透過內皮源性一氧化氮釋放來保護心血管系統。

過度表現克洛素的小鼠，平均壽命會較一般小數多出19%至31%^[8]。克洛速基因的某些變異還與長壽和增進認知功能相關^[15]。

克洛素的作用機轉迄今未明，目前已知可以透過提升TRPV5（英語：TRPV5）和降低TRPC6（英語：TRPC6）的表達調控細胞的鈣平衡^[16]。此外，克洛素也會增加內向整流離子通道ROMK（英語：ROMK）的表達^[16]。克洛素缺乏的小鼠會會增加維他命D的製造^{[17][18][19][20]}。

參考文獻

1. GRCh38: Ensembl release 89: ENSG00000133116 - Ensembl, May 2017
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.
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.
6. Entrez Gene: klotho.
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.
8. 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.
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.
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.
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.^{[永久失效連結]}
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.
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)
16. 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.
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.
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.

延伸閱讀

• 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 , 編. 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.

外部連結

• Entrez Gene entry for Klotho
• GenAge entry for Klotho （頁面存檔備份，存於網際網路檔案館）

克洛素引用了美國國家醫學圖書館提供的資料，這些資料屬於公共領域。